The Experts below are selected from a list of 201 Experts worldwide ranked by ideXlab platform
Dulal Panda - One of the best experts on this subject based on the ideXlab platform.
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Microtubule Assembly dynamics an attractive target for anticancer drugs
Iubmb Life, 2008Co-Authors: Parminder Singh, Krishnan Rathinasamy, Renu Mohan, Dulal PandaAbstract:Microtubules, composed of αβ tubulin dimers, are dynamic polymers of eukaryotic cells. They play important roles in various cellular functions including mitosis. Microtubules exhibit differential dynamic behaviors during different phases of the cell cycle. Inhibition of the Microtubule Assembly dynamics causes cell cycle arrest leading to apoptosis; thus, qualifying them as important drug targets for treating several diseases including cancer, neuronal, fungal, and parasitic diseases. Although several Microtubule-targeted drugs are successfully being used in cancer chemotherapy, the development of resistance against these drugs and their inherent toxicities warrant the development of new agents with improved efficacy. Several antiMicrotubule agents are currently being evaluated for their possible uses in cancer chemotherapy. Benomyl, griseofulvin, and sulfonamides have been used as antifungal and antibacterial drugs. Recent reports have shown that these drugs have potent antitumor potential. These agents are shown to inhibit proliferation of different types of tumor cells and induce apoptosis by targeting Microtubule Assembly dynamics. However, unlike vincas and taxanes, which inhibit cancer cell proliferation in nanomolar concentration range, these agents act in micromolar range and are considered to have limited toxicities. Here, we suggest that these drugs may have a significant use in cancer chemotherapy when used in combination with other anticancer drugs. © 2008 IUBMB IUBMB Life, 60(6): 368–375, 2008
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dietary antioxidant curcumin inhibits Microtubule Assembly through tubulin binding
FEBS Journal, 2006Co-Authors: Kamlesh K Gupta, Shubhada S Bharne, Krishnan Rathinasamy, Nishigandha R Naik, Dulal PandaAbstract:Curcumin, a component of turmeric, has potent antitumor activity against several tumor types. However, its molecular target and mechanism of antiproliferative activity are not clear. Here, we identified curcumin as a novel antiMicrotubule agent. We have examined the effects of curcumin on cellular Microtubules and on reconstituted Microtubules in vitro. Curcumin inhibited HeLa and MCF-7 cell proliferation in a concentration-dependent manner with IC50 of 13.8 ± 0.7 µm and 12 ± 0.6 µm, respectively. At higher inhibitory concentrations (> 10 µm), curcumin induced significant depolymerization of interphase Microtubules and mitotic spindle Microtubules of HeLa and MCF-7 cells. However, at low inhibitory concentrations there were minimal effects on cellular Microtubules. It disrupted Microtubule Assembly in vitro, reduced GTPase activity, and induced tubulin aggregation. Curcumin bound to tubulin at a single site with a dissociation constant of 2.4 ± 0.4 µm and the binding of curcumin to tubulin induced conformational changes in tubulin. Colchicine and podophyllotoxin partly inhibited the binding of curcumin to tubulin, while vinblastine had no effect on the curcumin–tubulin interactions. The data together suggested that curcumin may inhibit cancer cells proliferation by perturbing Microtubule Assembly dynamics and may be used to develop efficacious curcumin analogues for cancer chemotherapy.
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the benzophenanthridine alkaloid sanguinarine perturbs Microtubule Assembly dynamics through tubulin binding a possible mechanism for its antiproliferative activity
FEBS Journal, 2006Co-Authors: Manu Lopus, Dulal PandaAbstract:Sanguinarine has been shown to inhibit proliferation of several types of human cancer cell including multidrug-resistant cells, whereas it has minimal cytotoxicity against normal cells such as neutrophils and keratinocytes. By analyzing the antiproliferative activity of sanguinarine in relation to its effects on mitosis and Microtubule Assembly, we found that it inhibits cancer cell proliferation by a novel mechanism. It inhibited HeLa cell proliferation with a half-maximal inhibitory concentration of 1.6 ± 0.1 µm. In its lower effective inhibitory concentration range, sanguinarine depolymerized Microtubules of both interphase and mitotic cells and perturbed chromosome organization in mitotic HeLa cells. At concentrations of 2 µm, it induced bundling of interphase Microtubules and formation of granular tubulin aggregates. A brief exposure of HeLa cells to sanguinarine caused irreversible depolymerization of the Microtubules, inhibited cell proliferation, and induced cell death. However, in contrast with several other Microtubule-depolymerizing agents, sanguinarine did not arrest cell cycle progression at mitosis. In vitro, low concentrations of sanguinarine inhibited Microtubule Assembly. At higher concentrations (> 40 µm), it altered polymer morphology. Further, it induced aggregation of tubulin in the presence of Microtubule-associated proteins. The binding of sanguinarine to tubulin induces conformational changes in tubulin. Together, the results suggest that sanguinarine inhibits cell proliferation at least in part by perturbing Microtubule Assembly dynamics.
Manu Lopus - One of the best experts on this subject based on the ideXlab platform.
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the benzophenanthridine alkaloid sanguinarine perturbs Microtubule Assembly dynamics through tubulin binding a possible mechanism for its antiproliferative activity
FEBS Journal, 2006Co-Authors: Manu Lopus, Dulal PandaAbstract:Sanguinarine has been shown to inhibit proliferation of several types of human cancer cell including multidrug-resistant cells, whereas it has minimal cytotoxicity against normal cells such as neutrophils and keratinocytes. By analyzing the antiproliferative activity of sanguinarine in relation to its effects on mitosis and Microtubule Assembly, we found that it inhibits cancer cell proliferation by a novel mechanism. It inhibited HeLa cell proliferation with a half-maximal inhibitory concentration of 1.6 ± 0.1 µm. In its lower effective inhibitory concentration range, sanguinarine depolymerized Microtubules of both interphase and mitotic cells and perturbed chromosome organization in mitotic HeLa cells. At concentrations of 2 µm, it induced bundling of interphase Microtubules and formation of granular tubulin aggregates. A brief exposure of HeLa cells to sanguinarine caused irreversible depolymerization of the Microtubules, inhibited cell proliferation, and induced cell death. However, in contrast with several other Microtubule-depolymerizing agents, sanguinarine did not arrest cell cycle progression at mitosis. In vitro, low concentrations of sanguinarine inhibited Microtubule Assembly. At higher concentrations (> 40 µm), it altered polymer morphology. Further, it induced aggregation of tubulin in the presence of Microtubule-associated proteins. The binding of sanguinarine to tubulin induces conformational changes in tubulin. Together, the results suggest that sanguinarine inhibits cell proliferation at least in part by perturbing Microtubule Assembly dynamics.
John I. Clark - One of the best experts on this subject based on the ideXlab platform.
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Interactive Domains in the Molecular Chaperone Human aB Crystallin Modulate Microtubule Assembly and
2020Co-Authors: Disassembly G. Ghosh, Scott A. Houck, John I. ClarkAbstract:Background. Small heat shock proteins regulate Microtubule Assembly during cell proliferation and in response to stress through interactions that are poorly understood. Methodology. Novel functions for five interactive sequences in the small heat shock protein and molecular chaperone, human aB crystallin, were investigated in the Assembly/disAssembly of Microtubules and aggregation of tubulin using synthetic peptides and mutants of human aB crystallin. Principal Findings. The interactive sequence 113FISREFHR120 exposed on the surface of aB crystallin decreased Microtubule Assembly by ,45%. In contrast, the interactive sequences, 131LTITSSLSSDGV142 and 156ERTIPITRE164, corresponding to the b8 strand and the Cterminal extension respectively, which are involved in complex formation, increased Microtubule Assembly by ,34–45%. The aB crystallin peptides, 113FISREFHR120 and 156ERTIPITRE164, inhibited Microtubule disAssembly by ,26–36%, and the peptides 113FISREFHR120 and 131LTITSSLSSDGV142 decreased the thermal aggregation of tubulin by ,42–44%. The 131LTITSSLSSDGV142 and 156ERTIPITRE164 peptides were more effective than the widely used anti-cancer drug, Paclitaxel, in modulating tubulin«Microtubule dynamics. Mutagenesis of these interactive sequences in wt human aB crystallin confirmed the effects of the aB crystallin peptides on Microtubule Assembly/disAssembly and tubulin aggregation. The regulation of Microtubule Assembly by aB crystallin varied over a narrow range of concentrations. The Assembly of Microtubules was maximal at aB crystallin to tubulin molar ratios between 1:4 and 2:1, while molar ratios .2:1 inhibited Microtubule Assembly. Conclusions and Significance. Interactive sequences on the surface of human aB crystallin collectively modulate Microtubule Assembly through a dynamic subunit exchange mechanism that depends on the concentration and ratio of aB crystallin to tubulin. These are the first experimental results in support of the functional importance of the dynamic subunit model of small heat shock proteins.
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Interactive Domains in the Molecular Chaperone Human αB Crystallin Modulate Microtubule Assembly and DisAssembly
PLOS ONE, 2007Co-Authors: Joy G. Ghosh, Scott A. Houck, John I. ClarkAbstract:Background Small heat shock proteins regulate Microtubule Assembly during cell proliferation and in response to stress through interactions that are poorly understood. Methodology Novel functions for five interactive sequences in the small heat shock protein and molecular chaperone, human αB crystallin, were investigated in the Assembly/disAssembly of Microtubules and aggregation of tubulin using synthetic peptides and mutants of human αB crystallin. Principal Findings The interactive sequence 113FISREFHR120 exposed on the surface of αB crystallin decreased Microtubule Assembly by ~45%. In contrast, the interactive sequences, 131LTITSSLSSDGV142 and 156ERTIPITRE164, corresponding to the β8 strand and the C-terminal extension respectively, which are involved in complex formation, increased Microtubule Assembly by ~34–45%. The αB crystallin peptides, 113FISREFHR120 and 156ERTIPITRE164, inhibited Microtubule disAssembly by ~26–36%, and the peptides 113FISREFHR120 and 131LTITSSLSSDGV142 decreased the thermal aggregation of tubulin by ~42–44%. The 131LTITSSLSSDGV142 and 156ERTIPITRE164 peptides were more effective than the widely used anti-cancer drug, Paclitaxel, in modulating tubulin↔Microtubule dynamics. Mutagenesis of these interactive sequences in wt human αB crystallin confirmed the effects of the αB crystallin peptides on Microtubule Assembly/disAssembly and tubulin aggregation. The regulation of Microtubule Assembly by αB crystallin varied over a narrow range of concentrations. The Assembly of Microtubules was maximal at αB crystallin to tubulin molar ratios between 1:4 and 2:1, while molar ratios >2:1 inhibited Microtubule Assembly. Conclusions and Significance Interactive sequences on the surface of human αB crystallin collectively modulate Microtubule Assembly through a dynamic subunit exchange mechanism that depends on the concentration and ratio of αB crystallin to tubulin. These are the first experimental results in support of the functional importance of the dynamic subunit model of small heat shock proteins.
Isabelle Vernos - One of the best experts on this subject based on the ideXlab platform.
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The sequential activation of the mitotic Microtubule Assembly pathways favors bipolar spindle formation
Molecular Biology of the Cell, 2016Co-Authors: Tommaso Cavazza, Paolo Malgaretti, Isabelle VernosAbstract:Centrosome maturation is the process by which the duplicated centrosomes re- cruit pericentriolar components and increase their Microtubule nucleation activity before mi- tosis. The role of this process in cells entering mitosis has been mostly related to the separa- tion of the duplicated centrosomes and thereby to the Assembly of a bipolar spindle. However, spindles can form without centrosomes. In fact, all cells, whether they have centro- somes or not, rely on chromatin-driven Microtubule Assembly to form a spindle. To test whether the sequential activation of these Microtubule Assembly pathways, defined by cen - trosome maturation and nuclear envelope breakdown, plays any role in spindle Assembly, we combined experiments in tissue culture cells and Xenopus laevis egg extracts with a mathe- matical model. We found that interfering with the sequential activation of the Microtubule Assembly pathways compromises bipolar spindle Assembly in tissue culture cells but not in X. laevis egg extracts. Our data suggest a novel function for centrosome maturation that deter- mines the contribution of the chromosomal Microtubule Assembly pathway and favors bipolar spindle formation in most animal cells in which tubulin is in limiting amounts.
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chromosome induced Microtubule Assembly mediated by tpx2 is required for spindle formation in hela cells
Nature Cell Biology, 2002Co-Authors: Oliver J Gruss, Hideki Yokoyama, Eric Karsenti, Iain W. Mattaj, Malte Wittmann, Rainer Pepperkok, Thomas A Kufer, Herman H W Sillje, Isabelle VernosAbstract:Chromosome-induced Microtubule Assembly mediated by TPX2 is required for spindle formation in HeLa cells
Krishnan Rathinasamy - One of the best experts on this subject based on the ideXlab platform.
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Microtubule Assembly dynamics an attractive target for anticancer drugs
Iubmb Life, 2008Co-Authors: Parminder Singh, Krishnan Rathinasamy, Renu Mohan, Dulal PandaAbstract:Microtubules, composed of αβ tubulin dimers, are dynamic polymers of eukaryotic cells. They play important roles in various cellular functions including mitosis. Microtubules exhibit differential dynamic behaviors during different phases of the cell cycle. Inhibition of the Microtubule Assembly dynamics causes cell cycle arrest leading to apoptosis; thus, qualifying them as important drug targets for treating several diseases including cancer, neuronal, fungal, and parasitic diseases. Although several Microtubule-targeted drugs are successfully being used in cancer chemotherapy, the development of resistance against these drugs and their inherent toxicities warrant the development of new agents with improved efficacy. Several antiMicrotubule agents are currently being evaluated for their possible uses in cancer chemotherapy. Benomyl, griseofulvin, and sulfonamides have been used as antifungal and antibacterial drugs. Recent reports have shown that these drugs have potent antitumor potential. These agents are shown to inhibit proliferation of different types of tumor cells and induce apoptosis by targeting Microtubule Assembly dynamics. However, unlike vincas and taxanes, which inhibit cancer cell proliferation in nanomolar concentration range, these agents act in micromolar range and are considered to have limited toxicities. Here, we suggest that these drugs may have a significant use in cancer chemotherapy when used in combination with other anticancer drugs. © 2008 IUBMB IUBMB Life, 60(6): 368–375, 2008
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dietary antioxidant curcumin inhibits Microtubule Assembly through tubulin binding
FEBS Journal, 2006Co-Authors: Kamlesh K Gupta, Shubhada S Bharne, Krishnan Rathinasamy, Nishigandha R Naik, Dulal PandaAbstract:Curcumin, a component of turmeric, has potent antitumor activity against several tumor types. However, its molecular target and mechanism of antiproliferative activity are not clear. Here, we identified curcumin as a novel antiMicrotubule agent. We have examined the effects of curcumin on cellular Microtubules and on reconstituted Microtubules in vitro. Curcumin inhibited HeLa and MCF-7 cell proliferation in a concentration-dependent manner with IC50 of 13.8 ± 0.7 µm and 12 ± 0.6 µm, respectively. At higher inhibitory concentrations (> 10 µm), curcumin induced significant depolymerization of interphase Microtubules and mitotic spindle Microtubules of HeLa and MCF-7 cells. However, at low inhibitory concentrations there were minimal effects on cellular Microtubules. It disrupted Microtubule Assembly in vitro, reduced GTPase activity, and induced tubulin aggregation. Curcumin bound to tubulin at a single site with a dissociation constant of 2.4 ± 0.4 µm and the binding of curcumin to tubulin induced conformational changes in tubulin. Colchicine and podophyllotoxin partly inhibited the binding of curcumin to tubulin, while vinblastine had no effect on the curcumin–tubulin interactions. The data together suggested that curcumin may inhibit cancer cells proliferation by perturbing Microtubule Assembly dynamics and may be used to develop efficacious curcumin analogues for cancer chemotherapy.