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  1. Xianghua Zhang, Hweon Park, Sung-Sik Han, Jung Woo Kim and Chang-Young Jang.
    ER$\alpha$ regulates chromosome alignment and spindle dynamics during mitosis.. Biochemical and biophysical research communications 456(4):919–25, January 2015.
    Abstract Estrogen receptors are activated by the hormone estrogen and they control cell growth by altering gene expression as a transcription factor. So far two estrogen receptors have been found: ER$\alpha$ and ER$\beta$. Estrogen receptors are also implicated in the development and progression of breast cancer. Here, we found that ER$\alpha$ localized on the spindle and spindle poles at the metaphase during mitosis. Depletion of ER$\alpha$ generated unaligned chromosomes in metaphase cells and lagging chromosomes in anaphase cells in a transcription-independent manner. Furthermore, the levels of $\beta$-tubulin and $\gamma$-tubulin were reduced in ER$\alpha$-depleted cells. Consistent with this, polymerization of microtubules in ER$\alpha$-depleted cells and turnover rate of $\alpha$/$\beta$-tubulin were decreased than in control cells. We suggest that ER$\alpha$ regulates chromosome alignment and spindle dynamics by stabilizing microtubules during mitosis.
    URL, DOI BibTeX

    @article{Zhang2015,
    	abstract = "Estrogen receptors are activated by the hormone estrogen and they control cell growth by altering gene expression as a transcription factor. So far two estrogen receptors have been found: ER$\alpha$ and ER$\beta$. Estrogen receptors are also implicated in the development and progression of breast cancer. Here, we found that ER$\alpha$ localized on the spindle and spindle poles at the metaphase during mitosis. Depletion of ER$\alpha$ generated unaligned chromosomes in metaphase cells and lagging chromosomes in anaphase cells in a transcription-independent manner. Furthermore, the levels of $\beta$-tubulin and $\gamma$-tubulin were reduced in ER$\alpha$-depleted cells. Consistent with this, polymerization of microtubules in ER$\alpha$-depleted cells and turnover rate of $\alpha$/$\beta$-tubulin were decreased than in control cells. We suggest that ER$\alpha$ regulates chromosome alignment and spindle dynamics by stabilizing microtubules during mitosis.",
    	author = "Zhang, Xianghua and Park, Hweon and Han, Sung-Sik and Kim, Jung Woo and Jang, Chang-Young",
    	doi = "10.1016/j.bbrc.2014.12.062",
    	issn = "1090-2104",
    	journal = "Biochemical and biophysical research communications",
    	month = "jan",
    	number = 4,
    	pages = "919--25",
    	pmid = 25534852,
    	title = "{ER$\alpha$ regulates chromosome alignment and spindle dynamics during mitosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25534852",
    	volume = 456,
    	year = 2015
    }
    
  2. Geethu Emily Thomas, Jamuna S Sreeja, K K Gireesh, Hindol Gupta and Tapas K Manna.
    +TIP EB1 downregulates paclitaxel‑induced proliferation inhibition and apoptosis in breast cancer cells through inhibition of paclitaxel binding on microtubules.. International journal of oncology 46(1):133–46, January 2015.
    Abstract Microtubule plus‑end‑binding protein (+TIP) EB1 has been shown to be upregulated in breast cancer cells and promote breast tumor growth in vivo. However, its effect on the cellular actions of microtubule‑targeted drugs in breast cancer cells has remained poorly understood. By using cellular and biochemical assays, we demonstrate that EB1 plays a critical role in regulating the sensitivity of breast cancer cells to anti‑microtubule drug, paclitaxel (PTX). Cell viability assays revealed that EB1 expression in the breast cancer cell lines correlated with the reduction of their sensitivity to PTX. Knockdown of EB1 by enzymatically‑prepared siRNA pools (esiRNAs) increased PTX‑induced cytotoxicity and sensitized cells to PTX‑induced apoptosis in three breast cancer cell lines, MCF‑7, MDA MB‑231 and T47D. Apoptosis was associated with activation of caspase‑9 and an increase in the cleavage of poly(ADP‑ribose) polymerase (PARP). p53 and Bax were upregulated and Bcl2 was downregulated in the EB1‑depleted PTX‑treated MCF‑7 cells, indicating that the apoptosis occurs via a p53‑dependent pathway. Following its upregulation, the nuclear accumulation of p53 and its association with cellular microtubules were increased. EB1 depletion increased PTX‑induced microtubule bundling in the interphase cells and induced formation of multiple spindle foci with abnormally elongated spindles in the mitotic MCF‑7 cells, indicating that loss of EB1 promotes PTX‑induced stabilization of microtubules. EB1 inhibited PTX‑induced microtubule polymerization and diminished PTX binding to microtubules in vitro, suggesting that it modulates the binding sites of PTX at the growing microtubule ends. Results demonstrate that EB1 downregulates inhibition of PTX‑induced proliferation and apoptosis in breast cancer cells through a mechanism in which it impairs PTX‑mediated stabilization of microtubule polymerization and inhibits PTX binding on microtubules.
    URL, DOI BibTeX

    @article{Thomas2015,
    	abstract = "Microtubule plus‑end‑binding protein (+TIP) EB1 has been shown to be upregulated in breast cancer cells and promote breast tumor growth in vivo. However, its effect on the cellular actions of microtubule‑targeted drugs in breast cancer cells has remained poorly understood. By using cellular and biochemical assays, we demonstrate that EB1 plays a critical role in regulating the sensitivity of breast cancer cells to anti‑microtubule drug, paclitaxel (PTX). Cell viability assays revealed that EB1 expression in the breast cancer cell lines correlated with the reduction of their sensitivity to PTX. Knockdown of EB1 by enzymatically‑prepared siRNA pools (esiRNAs) increased PTX‑induced cytotoxicity and sensitized cells to PTX‑induced apoptosis in three breast cancer cell lines, MCF‑7, MDA MB‑231 and T47D. Apoptosis was associated with activation of caspase‑9 and an increase in the cleavage of poly(ADP‑ribose) polymerase (PARP). p53 and Bax were upregulated and Bcl2 was downregulated in the EB1‑depleted PTX‑treated MCF‑7 cells, indicating that the apoptosis occurs via a p53‑dependent pathway. Following its upregulation, the nuclear accumulation of p53 and its association with cellular microtubules were increased. EB1 depletion increased PTX‑induced microtubule bundling in the interphase cells and induced formation of multiple spindle foci with abnormally elongated spindles in the mitotic MCF‑7 cells, indicating that loss of EB1 promotes PTX‑induced stabilization of microtubules. EB1 inhibited PTX‑induced microtubule polymerization and diminished PTX binding to microtubules in vitro, suggesting that it modulates the binding sites of PTX at the growing microtubule ends. Results demonstrate that EB1 downregulates inhibition of PTX‑induced proliferation and apoptosis in breast cancer cells through a mechanism in which it impairs PTX‑mediated stabilization of microtubule polymerization and inhibits PTX binding on microtubules.",
    	author = "Thomas, Geethu Emily and Sreeja, Jamuna S and Gireesh, K K and Gupta, Hindol and Manna, Tapas K",
    	doi = "10.3892/ijo.2014.2701",
    	issn = "1791-2423",
    	journal = "International journal of oncology",
    	month = "jan",
    	number = 1,
    	pages = "133--46",
    	pmid = 25310526,
    	title = "{+TIP EB1 downregulates paclitaxel‑induced proliferation inhibition and apoptosis in breast cancer cells through inhibition of paclitaxel binding on microtubules.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25310526",
    	volume = 46,
    	year = 2015
    }
    
  3. Agnieszka Marczak and Aneta Rogalska.
    TUBB3 role in the response of tumor cells to epothilones and taxanes.. Postȩpy higieny i medycyny doświadczalnej (Online) 69:158–64, January 2015.
    Abstract Because of increased incidence of cancer and the development of resistance after treatment with typical drugs, new insights into the mechanisms of action of individual compounds are extremely valuable. In this article, we focus on taxanes, drugs belonging to the group of microtubule stabilizers, and their new generation - epothilones. Facing the fact that the molecular target for these compounds are microtubules, our attention was focused primarily on the role of overexpression of one of tubulin isotypes in response of tumor cells, particularly ovarian cancer to treatment with these compounds. On the basis of the literature data it can be concluded that one reason for the ineffectiveness of taxane is the resistance growing in the case of overexpression of b-tubulin class III- (TUBB3). Epothilones, however, due to their ability to bind equally to b-tubulin class I and III are effective in these cells, giving them an advantage over taxanes. It is necessary to emphasize the role of mikroRNA, transcription factors and other proteins associated with the activation of microtubules in development of resistance to taxanes and overcoming the resistance of the epothilones. Particularly interesting tubuseems to be the link between expression of TUBB3 and Glis proteins, which are end-effectors of Hedgehog pathway. Thanks to the confirmation that Gli1 overexpression is associated with decreased response to chemotherapy, it was possible to sensitize cells to epothilones after addition a suitable inhibitor.
    URL BibTeX

    @article{Marczak2015,
    	abstract = "Because of increased incidence of cancer and the development of resistance after treatment with typical drugs, new insights into the mechanisms of action of individual compounds are extremely valuable. In this article, we focus on taxanes, drugs belonging to the group of microtubule stabilizers, and their new generation - epothilones. Facing the fact that the molecular target for these compounds are microtubules, our attention was focused primarily on the role of overexpression of one of tubulin isotypes in response of tumor cells, particularly ovarian cancer to treatment with these compounds. On the basis of the literature data it can be concluded that one reason for the ineffectiveness of taxane is the resistance growing in the case of overexpression of b-tubulin class III- (TUBB3). Epothilones, however, due to their ability to bind equally to b-tubulin class I and III are effective in these cells, giving them an advantage over taxanes. It is necessary to emphasize the role of mikroRNA, transcription factors and other proteins associated with the activation of microtubules in development of resistance to taxanes and overcoming the resistance of the epothilones. Particularly interesting tubuseems to be the link between expression of TUBB3 and Glis proteins, which are end-effectors of Hedgehog pathway. Thanks to the confirmation that Gli1 overexpression is associated with decreased response to chemotherapy, it was possible to sensitize cells to epothilones after addition a suitable inhibitor.",
    	author = "Marczak, Agnieszka and Rogalska, Aneta",
    	issn = "1732-2693",
    	journal = "Postȩpy higieny i medycyny do\'{s}wiadczalnej (Online)",
    	month = "jan",
    	pages = "158--64",
    	pmid = 25661915,
    	title = "{TUBB3 role in the response of tumor cells to epothilones and taxanes.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25661915",
    	volume = 69,
    	year = 2015
    }
    
  4. Xiantao Li, Ximu Hu, Xiaoqing Li and Xuran Hao.
    Overexpression of Tau Downregulated the mRNA Levels of Kv Channels and Improved Proliferation in N2A Cells.. PloS one 10(1):e0116628, January 2015.
    Abstract Microtubule binding protein tau has a crucial function in promoting the assembly and stabilization of microtubule. Besides tuning the action potentials, voltage-gated K+ channels (Kv) are important for cell proliferation and appear to play a role in the development of cancer. However, little is known about the possible interaction of tau with Kv channels in various tissues. In the present study, tau plasmids were transiently transfected into mouse neuroblastoma N2A cells to explore the possible linkages between tau and Kv channels. This treatment led to a downregulation of mRNA levels of several Kv channels, including Kv2.1, Kv3.1, Kv4.1, Kv9.2, and KCNH4, but no significant alteration was observed for Kv5.1 and KCNQ4. Furthermore, the macroscopic currents through Kv channels were reduced by 36.5% at +60 mV in tau-tranfected N2A cells. The proliferation rates of N2A cells were also improved by the induction of tau expression and the incubation of TEA (tetraethylammonium) for 48 h by 120.9% and 149.3%, respectively. Following the cotransfection with tau in HEK293 cells, the mRNA levels and corresponding currents of Kv2.1 were significantly declined compared with single Kv2.1 transfection. Our data indicated that overexpression of tau declined the mRNA levels of Kv channels and related currents. The effects of tau overexpression on Kv channels provided an alternative explanation for low sensitivity to anti-cancer chemicals in some specific cancer tissues.
    URL, DOI BibTeX

    @article{Li2015a,
    	abstract = "Microtubule binding protein tau has a crucial function in promoting the assembly and stabilization of microtubule. Besides tuning the action potentials, voltage-gated K+ channels (Kv) are important for cell proliferation and appear to play a role in the development of cancer. However, little is known about the possible interaction of tau with Kv channels in various tissues. In the present study, tau plasmids were transiently transfected into mouse neuroblastoma N2A cells to explore the possible linkages between tau and Kv channels. This treatment led to a downregulation of mRNA levels of several Kv channels, including Kv2.1, Kv3.1, Kv4.1, Kv9.2, and KCNH4, but no significant alteration was observed for Kv5.1 and KCNQ4. Furthermore, the macroscopic currents through Kv channels were reduced by 36.5\% at +60 mV in tau-tranfected N2A cells. The proliferation rates of N2A cells were also improved by the induction of tau expression and the incubation of TEA (tetraethylammonium) for 48 h by 120.9\% and 149.3\%, respectively. Following the cotransfection with tau in HEK293 cells, the mRNA levels and corresponding currents of Kv2.1 were significantly declined compared with single Kv2.1 transfection. Our data indicated that overexpression of tau declined the mRNA levels of Kv channels and related currents. The effects of tau overexpression on Kv channels provided an alternative explanation for low sensitivity to anti-cancer chemicals in some specific cancer tissues.",
    	author = "Li, Xiantao and Hu, Ximu and Li, Xiaoqing and Hao, Xuran",
    	doi = "10.1371/journal.pone.0116628",
    	issn = "1932-6203",
    	journal = "PloS one",
    	month = "jan",
    	number = 1,
    	pages = "e0116628",
    	pmid = 25590133,
    	title = "{Overexpression of Tau Downregulated the mRNA Levels of Kv Channels and Improved Proliferation in N2A Cells.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4295873\&tool=pmcentrez\&rendertype=abstract",
    	volume = 10,
    	year = 2015
    }
    
  5. Ai-Jun Li, Yue-Hua Zheng, Guo-Dong Liu, Wei-Sheng Liu, Pei-Cheng Cao and Zhen-Fu Bu.
    Efficient delivery of docetaxel for the treatment of brain tumors by cyclic RGD-tagged polymeric micelles.. Molecular medicine reports 11(4):3078–86, 2015.
    Abstract The treatment of glioblastoma, and other types of brain cancer, is limited due to the poor transport of drugs across the blood brain barrier and poor penetration of the blood‑brain‑tumor barrier. In the present study, cyclic Arginine‑Glycine‑Aspartic acid‑D‑Tyrosine‑Lysine [c(RGDyK)], that has a high binding affinity to integrin $\alpha$v$\beta$3 receptors, that are overexpressed in glioblastoma cancers, was employed as a novel approach to target cancer by delivering therapeutic molecules intracellularly. The c(RGDyK)/docetaxel polylactic acid‑polyethylene glycol (DTX‑PLA‑PEG) micelle was prepared and characterized for various in vitro and in vivo parameters. The specific binding affinity of the Arginine‑Glycine‑Aspartic acid (RGD) micelles, to the integrin receptor, enhanced the intracellular accumulation of DTX, and markedly increased its cytotoxic efficacy. The effect of microtubule stabilization was evident in the inhibition of glioma spheroid volume. Upon intravenous administration, c(RGDyK)/DTX‑PLA‑PEG showed enhanced accumulation in brain tumor tissues through active internalization, whereas non‑targeted micelles showed limited transport ability. Furthermore, RGD‑linked micelles showed marked anti‑glioma activity in U87MG malignant glioma tumor xenografts, and significantly suppressed the growth of tumors without signs of systemic toxicity. In conclusion, the results of the present study suggest that ligand‑mediated drug delivery may improve the efficacy of brain cancer chemotherapy.
    URL, DOI BibTeX

    @article{Li2015,
    	abstract = "The treatment of glioblastoma, and other types of brain cancer, is limited due to the poor transport of drugs across the blood brain barrier and poor penetration of the blood‑brain‑tumor barrier. In the present study, cyclic Arginine‑Glycine‑Aspartic acid‑D‑Tyrosine‑Lysine [c(RGDyK)], that has a high binding affinity to integrin $\alpha$v$\beta$3 receptors, that are overexpressed in glioblastoma cancers, was employed as a novel approach to target cancer by delivering therapeutic molecules intracellularly. The c(RGDyK)/docetaxel polylactic acid‑polyethylene glycol (DTX‑PLA‑PEG) micelle was prepared and characterized for various in vitro and in vivo parameters. The specific binding affinity of the Arginine‑Glycine‑Aspartic acid (RGD) micelles, to the integrin receptor, enhanced the intracellular accumulation of DTX, and markedly increased its cytotoxic efficacy. The effect of microtubule stabilization was evident in the inhibition of glioma spheroid volume. Upon intravenous administration, c(RGDyK)/DTX‑PLA‑PEG showed enhanced accumulation in brain tumor tissues through active internalization, whereas non‑targeted micelles showed limited transport ability. Furthermore, RGD‑linked micelles showed marked anti‑glioma activity in U87MG malignant glioma tumor xenografts, and significantly suppressed the growth of tumors without signs of systemic toxicity. In conclusion, the results of the present study suggest that ligand‑mediated drug delivery may improve the efficacy of brain cancer chemotherapy.",
    	author = "Li, Ai-Jun and Zheng, Yue-Hua and Liu, Guo-Dong and Liu, Wei-Sheng and Cao, Pei-Cheng and Bu, Zhen-Fu",
    	doi = "10.3892/mmr.2014.3017",
    	issn = "1791-3004",
    	journal = "Molecular medicine reports",
    	month = "",
    	number = 4,
    	pages = "3078--86",
    	pmid = 25434368,
    	title = "{Efficient delivery of docetaxel for the treatment of brain tumors by cyclic RGD-tagged polymeric micelles.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25434368",
    	volume = 11,
    	year = 2015
    }
    
  6. Chetna Tyagi, Ankita Gupta, Sukriti Goyal, Jaspreet Dhanjal and Abhinav Grover.
    Fragment based group QSAR and molecular dynamics mechanistic studies on arylthioindole derivatives targeting the $\alpha$-$\beta$ interfacial site of human tubulin.. BMC genomics 15 Suppl 9:S3, December 2014.
    Abstract BACKGROUND: A number of microtubule disassembly blocking agents and inhibitors of tubulin polymerization have been elements of great interest in anti-cancer therapy, some of them even entering into the clinical trials. One such class of tubulin assembly inhibitors is of arylthioindole derivatives which results in effective microtubule disorganization responsible for cell apoptosis by interacting with the colchicine binding site of the $\beta$-unit of tubulin close to the interface with the $\alpha$ unit. We modelled the human tubulin $\beta$ unit (chain D) protein and performed docking studies to elucidate the detailed binding mode of actions associated with their inhibition. The activity enhancing structural aspects were evaluated using a fragment-based Group QSAR (G-QSAR) model and was validated statistically to determine its robustness. A combinatorial library was generated keeping the arylthioindole moiety as the template and their activities were predicted. RESULTS: The G-QSAR model obtained was statistically significant with r2 value of 0.85, cross validated correlation coefficient q2 value of 0.71 and pred_r2 (r2 value for test set) value of 0.89. A high F test value of 65.76 suggests robustness of the model. Screening of the combinatorial library on the basis of predicted activity values yielded two compounds HPI (predicted pIC50 = 6.042) and MSI (predicted pIC50 = 6.001) whose interactions with the D chain of modelled human tubulin protein were evaluated in detail. A toxicity evaluation resulted in MSI being less toxic in comparison to HPI. CONCLUSIONS: The study provides an insight into the crucial structural requirements and the necessary chemical substitutions required for the arylthioindole moiety to exhibit enhanced inhibitory activity against human tubulin. The two reported compounds HPI and MSI showed promising anti cancer activities and thus can be considered as potent leads against cancer. The toxicity evaluation of these compounds suggests that MSI is a promising therapeutic candidate. This study provided another stepping stone in the direction of evaluating tubulin inhibition and microtubule disassembly degeneration as viable targets for development of novel therapeutics against cancer.
    URL, DOI BibTeX

    @article{Tyagi2014,
    	abstract = "BACKGROUND: A number of microtubule disassembly blocking agents and inhibitors of tubulin polymerization have been elements of great interest in anti-cancer therapy, some of them even entering into the clinical trials. One such class of tubulin assembly inhibitors is of arylthioindole derivatives which results in effective microtubule disorganization responsible for cell apoptosis by interacting with the colchicine binding site of the $\beta$-unit of tubulin close to the interface with the $\alpha$ unit. We modelled the human tubulin $\beta$ unit (chain D) protein and performed docking studies to elucidate the detailed binding mode of actions associated with their inhibition. The activity enhancing structural aspects were evaluated using a fragment-based Group QSAR (G-QSAR) model and was validated statistically to determine its robustness. A combinatorial library was generated keeping the arylthioindole moiety as the template and their activities were predicted. RESULTS: The G-QSAR model obtained was statistically significant with r2 value of 0.85, cross validated correlation coefficient q2 value of 0.71 and pred\_r2 (r2 value for test set) value of 0.89. A high F test value of 65.76 suggests robustness of the model. Screening of the combinatorial library on the basis of predicted activity values yielded two compounds HPI (predicted pIC50 = 6.042) and MSI (predicted pIC50 = 6.001) whose interactions with the D chain of modelled human tubulin protein were evaluated in detail. A toxicity evaluation resulted in MSI being less toxic in comparison to HPI. CONCLUSIONS: The study provides an insight into the crucial structural requirements and the necessary chemical substitutions required for the arylthioindole moiety to exhibit enhanced inhibitory activity against human tubulin. The two reported compounds HPI and MSI showed promising anti cancer activities and thus can be considered as potent leads against cancer. The toxicity evaluation of these compounds suggests that MSI is a promising therapeutic candidate. This study provided another stepping stone in the direction of evaluating tubulin inhibition and microtubule disassembly degeneration as viable targets for development of novel therapeutics against cancer.",
    	author = "Tyagi, Chetna and Gupta, Ankita and Goyal, Sukriti and Dhanjal, Jaspreet and Grover, Abhinav",
    	doi = "10.1186/1471-2164-15-S9-S3",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Tyagi et al. - 2014 - Fragment based group QSAR and molecular dynamics mechanistic studies on arylthioindole derivatives targeting the $\alpha$.pdf:pdf",
    	issn = "1471-2164",
    	journal = "BMC genomics",
    	month = "dec",
    	pages = "S3",
    	pmid = 25521775,
    	title = "{Fragment based group QSAR and molecular dynamics mechanistic studies on arylthioindole derivatives targeting the $\alpha$-$\beta$ interfacial site of human tubulin.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4290613\&tool=pmcentrez\&rendertype=abstract",
    	volume = "15 Suppl 9",
    	year = 2014
    }
    
  7. Anne Martinez, Emmanuelle Soleilhac, Caroline Barette, Renaud Prudent, Gustavo Jabor Gozzi, Emilie Vassal-Stermann, Catherine Pillet, Attilio Di Pietro, Marie-Odile Fauvarque and Laurence Lafanechère.
    Novel Synthetic Pharmacophores Inducing a Stabilization of Cellular Microtubules.. Current cancer drug targets, December 2014.
    Abstract Microtubule drugs have been widely used in cancer chemotherapies. Although microtubules are subject to regulation by signal transduction mechanisms, their pharmacological modulation has so far relied on compounds that bind to the tubulin subunit. Using a cell-based assay designed to probe the microtubule polymerization status, we identified two pharmacophores, CM09 and CM10, as cell-permeable microtubule stabilizing agents. These synthetic compounds do not affect the assembly state of purified microtubules in vitro but they profoundly suppress microtubule dynamics in vivo. Moreover, they exert cytotoxic effects on several cancer cell lines including multidrug resistant cell lines. Therefore, these classes of compounds represent novel attractive leads for cancer chemotherapy.
    URL BibTeX

    @article{Martinez2014,
    	abstract = "Microtubule drugs have been widely used in cancer chemotherapies. Although microtubules are subject to regulation by signal transduction mechanisms, their pharmacological modulation has so far relied on compounds that bind to the tubulin subunit. Using a cell-based assay designed to probe the microtubule polymerization status, we identified two pharmacophores, CM09 and CM10, as cell-permeable microtubule stabilizing agents. These synthetic compounds do not affect the assembly state of purified microtubules in vitro but they profoundly suppress microtubule dynamics in vivo. Moreover, they exert cytotoxic effects on several cancer cell lines including multidrug resistant cell lines. Therefore, these classes of compounds represent novel attractive leads for cancer chemotherapy.",
    	author = "Martinez, Anne and Soleilhac, Emmanuelle and Barette, Caroline and Prudent, Renaud and Gozzi, Gustavo Jabor and Vassal-Stermann, Emilie and Pillet, Catherine and Pietro, Attilio Di and Fauvarque, Marie-Odile and Lafanech\`{e}re, Laurence",
    	issn = "1873-5576",
    	journal = "Current cancer drug targets",
    	month = "dec",
    	pmid = 25543663,
    	title = "{Novel Synthetic Pharmacophores Inducing a Stabilization of Cellular Microtubules.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25543663",
    	year = 2014
    }
    
  8. Dalip Kumar, N Maruthi Kumar, Mukund P Tantak, Maiko Ogura, Eriko Kusaka and Takeo Ito.
    Synthesis and identification of $\alpha$-cyano bis(indolyl)chalcones as novel anticancer agents.. Bioorganic & medicinal chemistry letters 24(22):5170–4, November 2014.
    Abstract Microwave-assisted synthesis of 23 $\alpha$-cyano bis(indolyl)chalcones (6a-w) and their in vitro anticancer activity against three human cancer cell lines have been discussed. Among the synthesized chalcones, compound 6n was found to be the most potent and selective against A549 lung cancer cell line (IC50 = 0.8 $\mu$M). In a preliminary mechanism of action studies some $\alpha$-cyano bis(indolyl)chalcones were found to enhance tubulin polymerization suggesting these compounds could act as microtubule stabilizing agents.
    URL, DOI BibTeX

    @article{Kumar2014,
    	abstract = "Microwave-assisted synthesis of 23 $\alpha$-cyano bis(indolyl)chalcones (6a-w) and their in vitro anticancer activity against three human cancer cell lines have been discussed. Among the synthesized chalcones, compound 6n was found to be the most potent and selective against A549 lung cancer cell line (IC50 = 0.8 $\mu$M). In a preliminary mechanism of action studies some $\alpha$-cyano bis(indolyl)chalcones were found to enhance tubulin polymerization suggesting these compounds could act as microtubule stabilizing agents.",
    	author = "Kumar, Dalip and {Maruthi Kumar}, N and Tantak, Mukund P and Ogura, Maiko and Kusaka, Eriko and Ito, Takeo",
    	doi = "10.1016/j.bmcl.2014.09.085",
    	issn = "1464-3405",
    	journal = "Bioorganic \& medicinal chemistry letters",
    	month = "nov",
    	number = 22,
    	pages = "5170--4",
    	pmid = 25442306,
    	title = "{Synthesis and identification of $\alpha$-cyano bis(indolyl)chalcones as novel anticancer agents.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25442306",
    	volume = 24,
    	year = 2014
    }
    
  9. B Sathish Kumar, Amit Kumar, Jyotsna Singh, Mohammad Hasanain, Arjun Singh, Kaneez Fatima, Dharmendra K Yadav, Vinay Shukla, Suaib Luqman, Feroz Khan, Debabrata Chanda, Jayanta Sarkar, Rituraj Konwar, Anila Dwivedi and Arvind S Negi.
    Synthesis of 2-alkoxy and 2-benzyloxy analogues of estradiol as anti-breast cancer agents through microtubule stabilization.. European journal of medicinal chemistry 86:740–51, October 2014.
    Abstract 2-Methoxyestradiol (2ME2) is an investigational anticancer drug. In the present study, 2-alkoxyesters/acid and 2-benzyloxy analogues of estradiol have been synthesized as analogues of 2ME2. Three of the derivatives exhibited significant anticancer activity against human breast cancer cell lines. The best analogue of the series i.e. 24 showed stabilization of tubulin polymerisation process. It was substantiated by confocal microscopy and molecular docking studies where 24 occupied 'paclitaxel binding pocket' to stabilize the polymerisation process. Compound 24 significantly inhibited MDA-MB-231 cells (IC50: 7 $\mu$M) and induced arrest of cell cycle and apoptosis in MDA-MB-231 cells. In acute oral toxicity, 24 was found to be non-toxic and well tolerated in Swiss albino mice up to 1000 mg/kg dose.
    URL, DOI BibTeX

    @article{SathishKumar2014,
    	abstract = "2-Methoxyestradiol (2ME2) is an investigational anticancer drug. In the present study, 2-alkoxyesters/acid and 2-benzyloxy analogues of estradiol have been synthesized as analogues of 2ME2. Three of the derivatives exhibited significant anticancer activity against human breast cancer cell lines. The best analogue of the series i.e. 24 showed stabilization of tubulin polymerisation process. It was substantiated by confocal microscopy and molecular docking studies where 24 occupied 'paclitaxel binding pocket' to stabilize the polymerisation process. Compound 24 significantly inhibited MDA-MB-231 cells (IC50: 7 $\mu$M) and induced arrest of cell cycle and apoptosis in MDA-MB-231 cells. In acute oral toxicity, 24 was found to be non-toxic and well tolerated in Swiss albino mice up to 1000 mg/kg dose.",
    	author = "{Sathish Kumar}, B and Kumar, Amit and Singh, Jyotsna and Hasanain, Mohammad and Singh, Arjun and Fatima, Kaneez and Yadav, Dharmendra K and Shukla, Vinay and Luqman, Suaib and Khan, Feroz and Chanda, Debabrata and Sarkar, Jayanta and Konwar, Rituraj and Dwivedi, Anila and Negi, Arvind S",
    	doi = "10.1016/j.ejmech.2014.09.033",
    	issn = "1768-3254",
    	journal = "European journal of medicinal chemistry",
    	month = "oct",
    	pages = "740--51",
    	pmid = 25238172,
    	title = "{Synthesis of 2-alkoxy and 2-benzyloxy analogues of estradiol as anti-breast cancer agents through microtubule stabilization.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25238172",
    	volume = 86,
    	year = 2014
    }
    
  10. Veronika Graml, Xenia Studera, Jonathan L D Lawson, Anatole Chessel, Marco Geymonat, Miriam Bortfeld-Miller, Thomas Walter, Laura Wagstaff, Eugenia Piddini and Rafael E Carazo-Salas.
    A genomic Multiprocess survey of machineries that control and link cell shape, microtubule organization, and cell-cycle progression.. Developmental cell 31(2):227–39, October 2014.
    Abstract Understanding cells as integrated systems requires that we systematically decipher how single genes affect multiple biological processes and how processes are functionally linked. Here, we used multiprocess phenotypic profiling, combining high-resolution 3D confocal microscopy and multiparametric image analysis, to simultaneously survey the fission yeast genome with respect to three key cellular processes: cell shape, microtubule organization, and cell-cycle progression. We identify, validate, and functionally annotate 262 genes controlling specific aspects of those processes. Of these, 62% had not been linked to these processes before and 35% are implicated in multiple processes. Importantly, we identify a conserved role for DNA-damage responses in controlling microtubule stability. In addition, we investigate how the processes are functionally linked. We show unexpectedly that disruption of cell-cycle progression does not necessarily affect cell size control and that distinct aspects of cell shape regulate microtubules and vice versa, identifying important systems-level links across these processes.
    URL, DOI BibTeX

    @article{Graml2014,
    	abstract = "Understanding cells as integrated systems requires that we systematically decipher how single genes affect multiple biological processes and how processes are functionally linked. Here, we used multiprocess phenotypic profiling, combining high-resolution 3D confocal microscopy and multiparametric image analysis, to simultaneously survey the fission yeast genome with respect to three key cellular processes: cell shape, microtubule organization, and cell-cycle progression. We identify, validate, and functionally annotate 262 genes controlling specific aspects of those processes. Of these, 62\% had not been linked to these processes before and 35\% are implicated in multiple processes. Importantly, we identify a conserved role for DNA-damage responses in controlling microtubule stability. In addition, we investigate how the processes are functionally linked. We show unexpectedly that disruption of cell-cycle progression does not necessarily affect cell size control and that distinct aspects of cell shape regulate microtubules and vice versa, identifying important systems-level links across these processes.",
    	author = "Graml, Veronika and Studera, Xenia and Lawson, Jonathan L D and Chessel, Anatole and Geymonat, Marco and Bortfeld-Miller, Miriam and Walter, Thomas and Wagstaff, Laura and Piddini, Eugenia and Carazo-Salas, Rafael E",
    	doi = "10.1016/j.devcel.2014.09.005",
    	issn = "1878-1551",
    	journal = "Developmental cell",
    	keywords = "Cell Cycle,Cell Cycle Proteins,Cell Cycle Proteins: genetics,Cell Cycle: genetics,Cell Division,Cell Shape,Cell Shape: genetics,DNA Damage,DNA Repair,Fungal Proteins,Fungal Proteins: genetics,Gene Knockout Techniques,Imaging, Three-Dimensional,Microscopy, Confocal,Microtubules,Microtubules: genetics,Microtubules: physiology,Protein Transport,Protein Transport: genetics,Schizosaccharomyces,Schizosaccharomyces pombe Proteins,Schizosaccharomyces pombe Proteins: genetics,Schizosaccharomyces: cytology,Schizosaccharomyces: genetics,Transcription, Genetic,Transcription, Genetic: genetics",
    	month = "oct",
    	number = 2,
    	pages = "227--39",
    	pmid = 25373780,
    	title = "{A genomic Multiprocess survey of machineries that control and link cell shape, microtubule organization, and cell-cycle progression.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25373780",
    	volume = 31,
    	year = 2014
    }
    
  11. Amelia L Parker, Maria Kavallaris and Joshua A McCarroll.
    Microtubules and their role in cellular stress in cancer.. Frontiers in oncology 4:153, January 2014.
    Abstract Microtubules are highly dynamic structures, which consist of $\alpha$- and $\beta$-tubulin heterodimers, and are involved in cell movement, intracellular trafficking, and mitosis. In the context of cancer, the tubulin family of proteins is recognized as the target of the tubulin-binding chemotherapeutics, which suppress the dynamics of the mitotic spindle to cause mitotic arrest and cell death. Importantly, changes in microtubule stability and the expression of different tubulin isotypes as well as altered post-translational modifications have been reported for a range of cancers. These changes have been correlated with poor prognosis and chemotherapy resistance in solid and hematological cancers. However, the mechanisms underlying these observations have remained poorly understood. Emerging evidence suggests that tubulins and microtubule-associated proteins may play a role in a range of cellular stress responses, thus conferring survival advantage to cancer cells. This review will focus on the importance of the microtubule-protein network in regulating critical cellular processes in response to stress. Understanding the role of microtubules in this context may offer novel therapeutic approaches for the treatment of cancer.
    URL, DOI BibTeX

    @article{Parker2014,
    	abstract = "Microtubules are highly dynamic structures, which consist of $\alpha$- and $\beta$-tubulin heterodimers, and are involved in cell movement, intracellular trafficking, and mitosis. In the context of cancer, the tubulin family of proteins is recognized as the target of the tubulin-binding chemotherapeutics, which suppress the dynamics of the mitotic spindle to cause mitotic arrest and cell death. Importantly, changes in microtubule stability and the expression of different tubulin isotypes as well as altered post-translational modifications have been reported for a range of cancers. These changes have been correlated with poor prognosis and chemotherapy resistance in solid and hematological cancers. However, the mechanisms underlying these observations have remained poorly understood. Emerging evidence suggests that tubulins and microtubule-associated proteins may play a role in a range of cellular stress responses, thus conferring survival advantage to cancer cells. This review will focus on the importance of the microtubule-protein network in regulating critical cellular processes in response to stress. Understanding the role of microtubules in this context may offer novel therapeutic approaches for the treatment of cancer.",
    	author = "Parker, Amelia L and Kavallaris, Maria and McCarroll, Joshua A",
    	doi = "10.3389/fonc.2014.00153",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Parker, Kavallaris, McCarroll - 2014 - Microtubules and their role in cellular stress in cancer.pdf:pdf",
    	issn = "2234-943X",
    	journal = "Frontiers in oncology",
    	month = "jan",
    	pages = 153,
    	pmid = 24995158,
    	title = "{Microtubules and their role in cellular stress in cancer.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4061531\&tool=pmcentrez\&rendertype=abstract",
    	volume = 4,
    	year = 2014
    }
    
  12. Ning Ding, Lingyan Ping, Yunfei Shi, Lixia Feng, Xiaohui Zheng, Yuqin Song and Jun Zhu.
    Thiamet-G-mediated inhibition of O-GlcNAcase sensitizes human leukemia cells to microtubule-stabilizing agent paclitaxel.. Biochemical and biophysical research communications 453(3):392–7, 2014.
    Abstract Although the microtubule-stabilizing agent paclitaxel has been widely used for treatment of several cancer types, particularly for the malignancies of epithelia origin, it only shows limited efficacy on hematological malignancies. Emerging roles of O-GlcNAcylation modification of proteins in various cancer types have implicated the key enzymes catalyzing this reversible modification as targets for cancer therapy. Here, we show that the highly selective O-GlcNAcase (OGA) inhibitor thiamet-G significantly sensitized human leukemia cell lines to paclitaxel, with an approximate 10-fold leftward shift of IC50. Knockdown of OGA by siRNAs or inhibition of OGA by thiamet-G did not influence the cell viability. Furthermore, we demonstrated that thiamet-G binds to OGA in competition with 4-methylumbelliferyl N-acetyl-$\beta$-d-glucosaminide dehydrate, an analogue of O-GlcNAc UDP, thereby suppressing the activity of OGA. Importantly, inhibition of OGA by thiamet-G decreased the phosphorylation of microtubule-associated protein Tau and caused alterations of microtubule network in cells. It is noteworthy that paclitaxel combined with thiamet-G resulted in more profound perturbations on microtubule stability than did either one alone, which may implicate the underlying mechanism of thiamet-G-mediated sensitization of leukemia cells to paclitaxel. These findings thus suggest that a regimen of paclitaxel combined with OGA inhibitor might be more effective for the treatment of human leukemia.
    URL, DOI BibTeX

    @article{Ding2014a,
    	abstract = "Although the microtubule-stabilizing agent paclitaxel has been widely used for treatment of several cancer types, particularly for the malignancies of epithelia origin, it only shows limited efficacy on hematological malignancies. Emerging roles of O-GlcNAcylation modification of proteins in various cancer types have implicated the key enzymes catalyzing this reversible modification as targets for cancer therapy. Here, we show that the highly selective O-GlcNAcase (OGA) inhibitor thiamet-G significantly sensitized human leukemia cell lines to paclitaxel, with an approximate 10-fold leftward shift of IC50. Knockdown of OGA by siRNAs or inhibition of OGA by thiamet-G did not influence the cell viability. Furthermore, we demonstrated that thiamet-G binds to OGA in competition with 4-methylumbelliferyl N-acetyl-$\beta$-d-glucosaminide dehydrate, an analogue of O-GlcNAc UDP, thereby suppressing the activity of OGA. Importantly, inhibition of OGA by thiamet-G decreased the phosphorylation of microtubule-associated protein Tau and caused alterations of microtubule network in cells. It is noteworthy that paclitaxel combined with thiamet-G resulted in more profound perturbations on microtubule stability than did either one alone, which may implicate the underlying mechanism of thiamet-G-mediated sensitization of leukemia cells to paclitaxel. These findings thus suggest that a regimen of paclitaxel combined with OGA inhibitor might be more effective for the treatment of human leukemia.",
    	author = "Ding, Ning and Ping, Lingyan and Shi, Yunfei and Feng, Lixia and Zheng, Xiaohui and Song, Yuqin and Zhu, Jun",
    	doi = "10.1016/j.bbrc.2014.09.097",
    	issn = "1090-2104",
    	journal = "Biochemical and biophysical research communications",
    	month = "",
    	number = 3,
    	pages = "392--7",
    	pmid = 25268318,
    	title = "{Thiamet-G-mediated inhibition of O-GlcNAcase sensitizes human leukemia cells to microtubule-stabilizing agent paclitaxel.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25268318",
    	volume = 453,
    	year = 2014
    }
    
  13. Ning Ding, Lingyan Ping, Lixia Feng, Xiaohui Zheng, Yuqin Song and Jun Zhu.
    Histone deacetylase 6 activity is critical for the metastasis of Burkitt's lymphoma cells.. Cancer cell international 14(1):139, January 2014.
    Abstract BACKGROUND: Burkitt's lymphoma is an aggressive malignancy with high risk of metastasis to extranodal sites, such as bone marrow and central nervous system. The prognosis of metastatic Burkitt's lymphoma is poor. Here we sought to identify a role of histone deacetylase 6 (HDAC6) in the metastasis of Burkitt's lymphoma cells. METHODS: Burkitt's lymphoma cells were pharmacologically treated with niltubacin, tubacin or sodium butyrate (NaB) or transfected with siRNAs to knock down the expression of HDAC6. Cell migration and invasion ability were measured by transwell assay, and cell cycle progression was analyzed by flow cytometry. Cell adhesion and proliferation was determined by CellTiter-Glo luminescent cell viability assay kit. Cell morphological alteration and microtubule stability were analyzed by immunofluorescence staining. Effect of niltubacin, tubacin and NaB on acetylated tubulin and siRNA efficacy were measured by western blotting. RESULTS: Suppression of histone deacetylase 6 activity significantly compromised the migration and invasion of Burkitt's lymphoma cells, without affecting cell proliferation and cell cycle progression. Mechanistic study revealed that HDAC6 modulated chemokine induced cell shape elongation and cell adhesion probably through its action on microtubule dynamics. CONCLUSIONS: We identified a critical role of HDAC6 in the metastasis of Burkitt's lymphoma cells, suggesting that pharmacological inhibition of HDAC6 could be a promising strategy for the management of metastatic Burkitt's lymphoma.
    URL, DOI BibTeX

    @article{Ding2014,
    	abstract = "BACKGROUND: Burkitt's lymphoma is an aggressive malignancy with high risk of metastasis to extranodal sites, such as bone marrow and central nervous system. The prognosis of metastatic Burkitt's lymphoma is poor. Here we sought to identify a role of histone deacetylase 6 (HDAC6) in the metastasis of Burkitt's lymphoma cells. METHODS: Burkitt's lymphoma cells were pharmacologically treated with niltubacin, tubacin or sodium butyrate (NaB) or transfected with siRNAs to knock down the expression of HDAC6. Cell migration and invasion ability were measured by transwell assay, and cell cycle progression was analyzed by flow cytometry. Cell adhesion and proliferation was determined by CellTiter-Glo luminescent cell viability assay kit. Cell morphological alteration and microtubule stability were analyzed by immunofluorescence staining. Effect of niltubacin, tubacin and NaB on acetylated tubulin and siRNA efficacy were measured by western blotting. RESULTS: Suppression of histone deacetylase 6 activity significantly compromised the migration and invasion of Burkitt's lymphoma cells, without affecting cell proliferation and cell cycle progression. Mechanistic study revealed that HDAC6 modulated chemokine induced cell shape elongation and cell adhesion probably through its action on microtubule dynamics. CONCLUSIONS: We identified a critical role of HDAC6 in the metastasis of Burkitt's lymphoma cells, suggesting that pharmacological inhibition of HDAC6 could be a promising strategy for the management of metastatic Burkitt's lymphoma.",
    	author = "Ding, Ning and Ping, Lingyan and Feng, Lixia and Zheng, Xiaohui and Song, Yuqin and Zhu, Jun",
    	doi = "10.1186/s12935-014-0139-z",
    	issn = "1475-2867",
    	journal = "Cancer cell international",
    	month = "jan",
    	number = 1,
    	pages = 139,
    	pmid = 25546298,
    	title = "{Histone deacetylase 6 activity is critical for the metastasis of Burkitt's lymphoma cells.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4276069\&tool=pmcentrez\&rendertype=abstract",
    	volume = 14,
    	year = 2014
    }
    
  14. Nadia D'Ambrosi, Simona Rossi, Valeria Gerbino and Mauro Cozzolino.
    Rac1 at the crossroad of actin dynamics and neuroinflammation in Amyotrophic Lateral Sclerosis.. Frontiers in cellular neuroscience 8:279, January 2014.
    Abstract Rac1 is a major player of the Rho family of small GTPases that controls multiple cell signaling pathways, such as the organization of cytoskeleton (including adhesion and motility), cell proliferation, apoptosis and activation of immune cells. In the nervous system, in particular, Rac1 GTPase plays a key regulatory function of both actin and microtubule cytoskeletal dynamics and thus it is central to axonal growth and stability, as well as dendrite and spine structural plasticity. Rac1 is also a crucial regulator of NADPH-dependent membrane oxidase (NOX), a prominent source of reactive oxygen species (ROS), thus having a central role in the inflammatory response and neurotoxicity mediated by microglia cells in the nervous system. As such, alterations in Rac1 activity might well be involved in the processes that give rise to Amyotrophic Lateral Sclerosis (ALS), a complex syndrome where cytoskeletal disturbances in motor neurons and redox alterations in the inflammatory compartment play pivotal and synergic roles in the final disease outcomes. Here we will discuss the genetic and mechanistic evidence indicating the relevance of Rac1 dysregulation in the pathogenesis of ALS.
    URL, DOI BibTeX

    @article{DAmbrosi2014,
    	abstract = "Rac1 is a major player of the Rho family of small GTPases that controls multiple cell signaling pathways, such as the organization of cytoskeleton (including adhesion and motility), cell proliferation, apoptosis and activation of immune cells. In the nervous system, in particular, Rac1 GTPase plays a key regulatory function of both actin and microtubule cytoskeletal dynamics and thus it is central to axonal growth and stability, as well as dendrite and spine structural plasticity. Rac1 is also a crucial regulator of NADPH-dependent membrane oxidase (NOX), a prominent source of reactive oxygen species (ROS), thus having a central role in the inflammatory response and neurotoxicity mediated by microglia cells in the nervous system. As such, alterations in Rac1 activity might well be involved in the processes that give rise to Amyotrophic Lateral Sclerosis (ALS), a complex syndrome where cytoskeletal disturbances in motor neurons and redox alterations in the inflammatory compartment play pivotal and synergic roles in the final disease outcomes. Here we will discuss the genetic and mechanistic evidence indicating the relevance of Rac1 dysregulation in the pathogenesis of ALS.",
    	author = "D'Ambrosi, Nadia and Rossi, Simona and Gerbino, Valeria and Cozzolino, Mauro",
    	doi = "10.3389/fncel.2014.00279",
    	issn = "1662-5102",
    	journal = "Frontiers in cellular neuroscience",
    	month = "jan",
    	pages = 279,
    	pmid = 25249940,
    	title = "{Rac1 at the crossroad of actin dynamics and neuroinflammation in Amyotrophic Lateral Sclerosis.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4157560\&tool=pmcentrez\&rendertype=abstract",
    	volume = 8,
    	year = 2014
    }
    
  15. Alyssa N Coyne, Bhavani Bagevalu Siddegowda, Patricia S Estes, Jeffrey Johannesmeyer, Tina Kovalik, Scott G Daniel, Antony Pearson, Robert Bowser and Daniela C Zarnescu.
    Futsch/MAP1B mRNA is a translational target of TDP-43 and is neuroprotective in a Drosophila model of amyotrophic lateral sclerosis.. The Journal of neuroscience : the official journal of the Society for Neuroscience 34(48):15962–74, 2014.
    Abstract TDP-43 is an RNA-binding protein linked to amyotrophic lateral sclerosis (ALS) that is known to regulate the splicing, transport, and storage of specific mRNAs into stress granules. Although TDP-43 has been shown to interact with translation factors, its role in protein synthesis remains unclear, and no in vivo translation targets have been reported to date. Here we provide evidence that TDP-43 associates with futsch mRNA in a complex and regulates its expression at the neuromuscular junction (NMJ) in Drosophila. In the context of TDP-43-induced proteinopathy, there is a significant reduction of futsch mRNA at the NMJ compared with motor neuron cell bodies where we find higher levels of transcript compared with controls. TDP-43 also leads to a significant reduction in Futsch protein expression at the NMJ. Polysome fractionations coupled with quantitative PCR experiments indicate that TDP-43 leads to a futsch mRNA shift from actively translating polysomes to nontranslating ribonuclear protein particles, suggesting that in addition to its effect on localization, TDP-43 also regulates the translation of futsch mRNA. We also show that futsch overexpression is neuroprotective by extending life span, reducing TDP-43 aggregation, and suppressing ALS-like locomotor dysfunction as well as NMJ abnormalities linked to microtubule and synaptic stabilization. Furthermore, the localization of MAP1B, the mammalian homolog of Futsch, is altered in ALS spinal cords in a manner similar to our observations in Drosophila motor neurons. Together, our results suggest a microtubule-dependent mechanism in motor neuron disease caused by TDP-43-dependent alterations in futsch mRNA localization and translation in vivo.
    URL, DOI BibTeX

    @article{Coyne2014,
    	abstract = "TDP-43 is an RNA-binding protein linked to amyotrophic lateral sclerosis (ALS) that is known to regulate the splicing, transport, and storage of specific mRNAs into stress granules. Although TDP-43 has been shown to interact with translation factors, its role in protein synthesis remains unclear, and no in vivo translation targets have been reported to date. Here we provide evidence that TDP-43 associates with futsch mRNA in a complex and regulates its expression at the neuromuscular junction (NMJ) in Drosophila. In the context of TDP-43-induced proteinopathy, there is a significant reduction of futsch mRNA at the NMJ compared with motor neuron cell bodies where we find higher levels of transcript compared with controls. TDP-43 also leads to a significant reduction in Futsch protein expression at the NMJ. Polysome fractionations coupled with quantitative PCR experiments indicate that TDP-43 leads to a futsch mRNA shift from actively translating polysomes to nontranslating ribonuclear protein particles, suggesting that in addition to its effect on localization, TDP-43 also regulates the translation of futsch mRNA. We also show that futsch overexpression is neuroprotective by extending life span, reducing TDP-43 aggregation, and suppressing ALS-like locomotor dysfunction as well as NMJ abnormalities linked to microtubule and synaptic stabilization. Furthermore, the localization of MAP1B, the mammalian homolog of Futsch, is altered in ALS spinal cords in a manner similar to our observations in Drosophila motor neurons. Together, our results suggest a microtubule-dependent mechanism in motor neuron disease caused by TDP-43-dependent alterations in futsch mRNA localization and translation in vivo.",
    	author = "Coyne, Alyssa N and Siddegowda, Bhavani Bagevalu and Estes, Patricia S and Johannesmeyer, Jeffrey and Kovalik, Tina and Daniel, Scott G and Pearson, Antony and Bowser, Robert and Zarnescu, Daniela C",
    	doi = "10.1523/JNEUROSCI.2526-14.2014",
    	issn = "1529-2401",
    	journal = "The Journal of neuroscience : the official journal of the Society for Neuroscience",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: prevention \& contro,Animals,Animals, Genetically Modified,DNA-Binding Proteins,DNA-Binding Proteins: biosynthesis,DNA-Binding Proteins: genetics,Disease Models, Animal,Drosophila,Drosophila Proteins,Drosophila Proteins: biosynthesis,Drosophila Proteins: genetics,Female,Gene Targeting,Gene Targeting: methods,Humans,Male,Microtubule-Associated Proteins,Microtubule-Associated Proteins: biosynthesis,Microtubule-Associated Proteins: genetics,Middle Aged,RNA, Messenger,RNA, Messenger: biosynthesis,RNA, Messenger: genetics",
    	month = "",
    	number = 48,
    	pages = "15962--74",
    	pmid = 25429138,
    	title = "{Futsch/MAP1B mRNA is a translational target of TDP-43 and is neuroprotective in a Drosophila model of amyotrophic lateral sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/25429138",
    	volume = 34,
    	year = 2014
    }
    
  16. Qiao-Hong Chen and David G I Kingston.
    Zampanolide and dactylolide: cytotoxic tubulin-assembly agents and promising anticancer leads.. Natural product reports 31(9):1202–26, 2014.
    Abstract Zampanolide is a marine natural macrolide and a recent addition to the family of microtubule-stabilizing cytotoxic agents. Zampanolide exhibits unique effects on tubulin assembly and is more potent than paclitaxel against several multi-drug resistant cancer cell lines. A high-resolution crystal structure of $\alpha$$\beta$-tubulin in complex with zampanolide explains how taxane-site microtubule-stabilizing agents promote microtubule assemble and stability. This review provides an overview of current developments of zampanolide and its related but less potent analogue dactylolide, covering their natural sources and isolation, structure and conformation, cytotoxic potential, structure-activity studies, mechanism of action, and syntheses.
    URL, DOI BibTeX

    @article{Chen2014,
    	abstract = "Zampanolide is a marine natural macrolide and a recent addition to the family of microtubule-stabilizing cytotoxic agents. Zampanolide exhibits unique effects on tubulin assembly and is more potent than paclitaxel against several multi-drug resistant cancer cell lines. A high-resolution crystal structure of $\alpha$$\beta$-tubulin in complex with zampanolide explains how taxane-site microtubule-stabilizing agents promote microtubule assemble and stability. This review provides an overview of current developments of zampanolide and its related but less potent analogue dactylolide, covering their natural sources and isolation, structure and conformation, cytotoxic potential, structure-activity studies, mechanism of action, and syntheses.",
    	author = "Chen, Qiao-Hong and Kingston, David G I",
    	doi = "10.1039/c4np00024b",
    	issn = "1460-4752",
    	journal = "Natural product reports",
    	month = "",
    	number = 9,
    	pages = "1202--26",
    	pmid = 24945566,
    	title = "{Zampanolide and dactylolide: cytotoxic tubulin-assembly agents and promising anticancer leads.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24945566",
    	volume = 31,
    	year = 2014
    }
    
  17. Tim N Beck, Emmanuelle Nicolas, Meghan C Kopp and Erica A Golemis.
    Adaptors for disorders of the brain? The cancer signaling proteins NEDD9, CASS4, and PTK2B in Alzheimer's disease.. Oncoscience 1(7):486–503, 2014.
    Abstract No treatment strategies effectively limit the progression of Alzheimer's disease (AD), a common and debilitating neurodegenerative disorder. The absence of viable treatment options reflects the fact that the pathophysiology and genotypic causes of the disease are not well understood. The advent of genome-wide association studies (GWAS) has made it possible to broadly investigate genotypic alterations driving phenotypic occurrences. Recent studies have associated single nucleotide polymorphisms (SNPs) in two paralogous scaffolding proteins, NEDD9 and CASS4, and the kinase PTK2B, with susceptibility to late-onset AD (LOAD). Intriguingly, NEDD9, CASS4, and PTK2B have been much studied as interacting partners regulating oncogenesis and metastasis, and all three are known to be active in the brain during development and in cancer. However, to date, the majority of studies of these proteins have emphasized their roles in the directly cancer relevant processes of migration and survival signaling. We here discuss evidence for roles of NEDD9, CASS4 and PTK2B in additional processes, including hypoxia, vascular changes, inflammation, microtubule stabilization and calcium signaling, as potentially relevant to the pathogenesis of LOAD. Reciprocally, these functions can better inform our understanding of the action of NEDD9, CASS4 and PTK2B in cancer.
    URL BibTeX

    @article{Beck2014,
    	abstract = "No treatment strategies effectively limit the progression of Alzheimer's disease (AD), a common and debilitating neurodegenerative disorder. The absence of viable treatment options reflects the fact that the pathophysiology and genotypic causes of the disease are not well understood. The advent of genome-wide association studies (GWAS) has made it possible to broadly investigate genotypic alterations driving phenotypic occurrences. Recent studies have associated single nucleotide polymorphisms (SNPs) in two paralogous scaffolding proteins, NEDD9 and CASS4, and the kinase PTK2B, with susceptibility to late-onset AD (LOAD). Intriguingly, NEDD9, CASS4, and PTK2B have been much studied as interacting partners regulating oncogenesis and metastasis, and all three are known to be active in the brain during development and in cancer. However, to date, the majority of studies of these proteins have emphasized their roles in the directly cancer relevant processes of migration and survival signaling. We here discuss evidence for roles of NEDD9, CASS4 and PTK2B in additional processes, including hypoxia, vascular changes, inflammation, microtubule stabilization and calcium signaling, as potentially relevant to the pathogenesis of LOAD. Reciprocally, these functions can better inform our understanding of the action of NEDD9, CASS4 and PTK2B in cancer.",
    	author = "Beck, Tim N and Nicolas, Emmanuelle and Kopp, Meghan C and Golemis, Erica A",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Beck et al. - 2014 - Adaptors for disorders of the brain The cancer signaling proteins NEDD9, CASS4, and PTK2B in Alzheimer's disease.pdf:pdf",
    	issn = "2331-4737",
    	journal = "Oncoscience",
    	month = "",
    	number = 7,
    	pages = "486--503",
    	pmid = 25594051,
    	title = "{Adaptors for disorders of the brain? The cancer signaling proteins NEDD9, CASS4, and PTK2B in Alzheimer's disease.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4278314\&tool=pmcentrez\&rendertype=abstract",
    	volume = 1,
    	year = 2014
    }
    
  18. Yan Jouroukhin, Regina Ostritsky, Yaniv Assaf, Galit Pelled, Eliezer Giladi and Illana Gozes.
    NAP (davunetide) modifies disease progression in a mouse model of severe neurodegeneration: protection against impairments in axonal transport.. Neurobiology of disease 56:79–94, 2013.
    Abstract NAP (davunetide) is a novel neuroprotective compound with mechanism of action that appears to involve microtubule (MT) stabilization and repair. To evaluate, for the first time, the impact of NAP on axonal transport in vivo and to translate it to neuroprotection in a severe neurodegeneration, the SOD1-G93A mouse model for amyotrophic lateral sclerosis (ALS) was used. Manganese-enhanced magnetic resonance imaging (MRI), estimating axonal transport rates, revealed a significant reduction of the anterograde axonal transport in the ALS mice compared to healthy control mice. Acute NAP treatment normalized axonal transport rates in these ALS mice. Tau hyperphosphorylation, associated with MT dysfunction and defective axonal transport, was discovered in the brains of the ALS mice and was significantly reduced by chronic NAP treatment. Furthermore, in healthy wild type (WT) mice, NAP reversed axonal transport disruption by colchicine, suggesting drug-dependent protection against axonal transport impairment through stabilization of the neuronal MT network. Histochemical analysis showed that chronic NAP treatment significantly protected spinal cord motor neurons against ALS-like pathology. Sequential MRI measurements, correlating brain structure with ALS disease progression, revealed a significant damage to the ventral tegmental area (VTA), indicative of impairments to the dopaminergic pathways relative to healthy controls. Chronic daily NAP treatment of the SOD1-G93A mice, initiated close to disease onset, delayed degeneration of the trigeminal, facial and hypoglossal motor nuclei as was significantly apparent at days 90-100 and further protected the VTA throughout life. Importantly, protection of the VTA was significantly correlated with longevity and overall, NAP treatment significantly prolonged life span in the ALS mice.
    URL, DOI BibTeX

    @article{Jouroukhin2013,
    	abstract = "NAP (davunetide) is a novel neuroprotective compound with mechanism of action that appears to involve microtubule (MT) stabilization and repair. To evaluate, for the first time, the impact of NAP on axonal transport in vivo and to translate it to neuroprotection in a severe neurodegeneration, the SOD1-G93A mouse model for amyotrophic lateral sclerosis (ALS) was used. Manganese-enhanced magnetic resonance imaging (MRI), estimating axonal transport rates, revealed a significant reduction of the anterograde axonal transport in the ALS mice compared to healthy control mice. Acute NAP treatment normalized axonal transport rates in these ALS mice. Tau hyperphosphorylation, associated with MT dysfunction and defective axonal transport, was discovered in the brains of the ALS mice and was significantly reduced by chronic NAP treatment. Furthermore, in healthy wild type (WT) mice, NAP reversed axonal transport disruption by colchicine, suggesting drug-dependent protection against axonal transport impairment through stabilization of the neuronal MT network. Histochemical analysis showed that chronic NAP treatment significantly protected spinal cord motor neurons against ALS-like pathology. Sequential MRI measurements, correlating brain structure with ALS disease progression, revealed a significant damage to the ventral tegmental area (VTA), indicative of impairments to the dopaminergic pathways relative to healthy controls. Chronic daily NAP treatment of the SOD1-G93A mice, initiated close to disease onset, delayed degeneration of the trigeminal, facial and hypoglossal motor nuclei as was significantly apparent at days 90-100 and further protected the VTA throughout life. Importantly, protection of the VTA was significantly correlated with longevity and overall, NAP treatment significantly prolonged life span in the ALS mice.",
    	author = "Jouroukhin, Yan and Ostritsky, Regina and Assaf, Yaniv and Pelled, Galit and Giladi, Eliezer and Gozes, Illana",
    	doi = "10.1016/j.nbd.2013.04.012",
    	issn = "1095-953X",
    	journal = "Neurobiology of disease",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: pathology,Amyotrophic Lateral Sclerosis: psychology,Animals,Axonal Transport,Axonal Transport: drug effects,Blotting, Western,Body Weight,Body Weight: drug effects,Brain,Brain: pathology,Contrast Media,Disease Progression,Female,Magnetic Resonance Imaging,Male,Manganese,Mice,Mice, Inbred C57BL,Neurodegenerative Diseases,Neurodegenerative Diseases: drug therapy,Neurodegenerative Diseases: pathology,Neurodegenerative Diseases: psychology,Neuroprotective Agents,Neuroprotective Agents: pharmacology,Oligopeptides,Oligopeptides: pharmacology,Phosphorylation,Psychomotor Performance,Psychomotor Performance: drug effects,Spinal Cord,Spinal Cord: pathology,Tubulin,Tubulin: metabolism,Tyrosine,Tyrosine: metabolism,Ventral Tegmental Area,Ventral Tegmental Area: pathology,tau Proteins,tau Proteins: metabolism",
    	month = "",
    	pages = "79--94",
    	pmid = 23631872,
    	title = "{NAP (davunetide) modifies disease progression in a mouse model of severe neurodegeneration: protection against impairments in axonal transport.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/23631872",
    	volume = 56,
    	year = 2013
    }
    
  19. Ewa Usarek, Magdalena Kuźma-Kozakiewicz, Birgit Schwalenstöcker, Beata Kaźmierczak, Christoph Münch, Albert C Ludolph and Anna Barańczyk-Kuźma.
    Tau isoforms expression in transgenic mouse model of amyotrophic lateral sclerosis.. Neurochemical research 31(5):597–602, 2006.
    Abstract Tau is a protein involved in regulation of microtubule stability, axonal differentiation and transport. Alteration of retrograde transport may lead to motor neuron degeneration. Thus alternative mRNA splicing and expression of tau isoforms were studied in a transgenic mouse model harboring the human SOD1 G93A mutation. The studies were performed on cortex, hippocampus and spinal cord of 64- and 120-day-old animals (presymptomatic and symptomatic stage) and wild type controls. Exon 10 was found in all studied tissues. The 2N isoform containing exons 2 and 3 (+2+3) and the 1N (+2-3) predominated over the 0N (-2-3) in brain regions of the studied mice. The 2N expression was significantly lower in cortex and hippocampus of symptomatic animals compared to analogue control tissues. The decrease in 2N expression resulted in lower levels of total tau mRNA and tau protein. No changes in tau expression were observed in spinal cord of studied animals.
    URL, DOI BibTeX

    @article{Usarek2006,
    	abstract = "Tau is a protein involved in regulation of microtubule stability, axonal differentiation and transport. Alteration of retrograde transport may lead to motor neuron degeneration. Thus alternative mRNA splicing and expression of tau isoforms were studied in a transgenic mouse model harboring the human SOD1 G93A mutation. The studies were performed on cortex, hippocampus and spinal cord of 64- and 120-day-old animals (presymptomatic and symptomatic stage) and wild type controls. Exon 10 was found in all studied tissues. The 2N isoform containing exons 2 and 3 (+2+3) and the 1N (+2-3) predominated over the 0N (-2-3) in brain regions of the studied mice. The 2N expression was significantly lower in cortex and hippocampus of symptomatic animals compared to analogue control tissues. The decrease in 2N expression resulted in lower levels of total tau mRNA and tau protein. No changes in tau expression were observed in spinal cord of studied animals.",
    	author = {Usarek, Ewa and Ku\'{z}ma-Kozakiewicz, Magdalena and Schwalenst\"{o}cker, Birgit and Ka\'{z}mierczak, Beata and M\"{u}nch, Christoph and Ludolph, Albert C and Barańczyk-Ku\'{z}ma, Anna},
    	doi = "10.1007/s11064-006-9057-3",
    	issn = "0364-3190",
    	journal = "Neurochemical research",
    	keywords = "Alternative Splicing,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Animals,Cerebral Cortex,Cerebral Cortex: metabolism,Disease Models, Animal,Exons,Hippocampus,Hippocampus: metabolism,Humans,Mice,Mice, Inbred C57BL,Mice, Transgenic,Protein Isoforms,Protein Isoforms: genetics,Protein Isoforms: metabolism,Spinal Cord,Spinal Cord: metabolism,Superoxide Dismutase,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism,tau Proteins,tau Proteins: genetics,tau Proteins: metabolism",
    	month = "",
    	number = 5,
    	pages = "597--602",
    	pmid = 16770730,
    	title = "{Tau isoforms expression in transgenic mouse model of amyotrophic lateral sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/16770730",
    	volume = 31,
    	year = 2006
    }
    
  20. F Letournel, A Bocquet, F Dubas, A Barthelaix and J Eyer.
    Stable tubule only polypeptides (STOP) proteins co-aggregate with spheroid neurofilaments in amyotrophic lateral sclerosis.. Journal of neuropathology and experimental neurology 62(12):1211–9, 2003.
    Abstract A major cytopathological hallmark of amyotrophic lateral sclerosis (ALS) is the presence of axonal spheroids containing abnormally accumulated neurofilaments. The mechanism of their formation, their contribution to the disease, and the possibility of other co-aggregated components are still enigmatic. Here we analyze the composition of such lesions with special reference to stable tubule only polypeptide (STOP), a protein responsible for microtubule cold stabilization. In normal human brain and spinal cord, the distribution of STOP proteins is uniform between the cytoplasm and neurites of neurons. However, all the neurofilament-rich spheroids present in the tissues of affected patients are intensely labeled with 3 different anti-STOP antibodies. Moreover, when neurofilaments and microtubules are isolated from spinal cord and brain, STOP proteins are systematically co-purified with neurofilaments. By SDS-PAGE analysis, no alteration of the migration profile of STOP proteins is observed in pathological samples. Other microtubular proteins, like tubulin or kinesin, are inconstantly present in spheroids, suggesting that a microtubule destabilizing process may be involved in the pathogenesis of ALS. These results indicate that the selective co-aggregation of neurofilament and STOP proteins represent a new cytopathological marker for spheroids.
    URL BibTeX

    @article{Letournel2003,
    	abstract = "A major cytopathological hallmark of amyotrophic lateral sclerosis (ALS) is the presence of axonal spheroids containing abnormally accumulated neurofilaments. The mechanism of their formation, their contribution to the disease, and the possibility of other co-aggregated components are still enigmatic. Here we analyze the composition of such lesions with special reference to stable tubule only polypeptide (STOP), a protein responsible for microtubule cold stabilization. In normal human brain and spinal cord, the distribution of STOP proteins is uniform between the cytoplasm and neurites of neurons. However, all the neurofilament-rich spheroids present in the tissues of affected patients are intensely labeled with 3 different anti-STOP antibodies. Moreover, when neurofilaments and microtubules are isolated from spinal cord and brain, STOP proteins are systematically co-purified with neurofilaments. By SDS-PAGE analysis, no alteration of the migration profile of STOP proteins is observed in pathological samples. Other microtubular proteins, like tubulin or kinesin, are inconstantly present in spheroids, suggesting that a microtubule destabilizing process may be involved in the pathogenesis of ALS. These results indicate that the selective co-aggregation of neurofilament and STOP proteins represent a new cytopathological marker for spheroids.",
    	author = "Letournel, F and Bocquet, A and Dubas, F and Barthelaix, A and Eyer, J",
    	issn = "0022-3069",
    	journal = "Journal of neuropathology and experimental neurology",
    	keywords = "Adult,Aged,Aged, 80 and over,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Animals,Brain,Brain: pathology,Cell Aggregation,Cell Aggregation: physiology,Female,Humans,Male,Mice,Microtubule-Associated Proteins,Microtubule-Associated Proteins: analysis,Microtubules,Microtubules: metabolism,Middle Aged,Neurofilament Proteins,Neurofilament Proteins: metabolism,Spheroids, Cellular,Spheroids, Cellular: metabolism,Spheroids, Cellular: pathology",
    	month = "",
    	number = 12,
    	pages = "1211--9",
    	pmid = 14692697,
    	title = "{Stable tubule only polypeptides (STOP) proteins co-aggregate with spheroid neurofilaments in amyotrophic lateral sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/14692697",
    	volume = 62,
    	year = 2003
    }