Current Search: Aurora-A Kinase (x)
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- Title
- SCREENING FOR ANTICANCER AGENTS TO INHIBIT MITOTIC KINASES AND PROLIFERATION OF METASTATIC PROSTATE CANCER CELLS.
- Creator
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Nguyen, Khoa, Chakrabarti, Ratna, University of Central Florida
- Abstract / Description
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Current treatments for prostate cancer (PCa) are marred with high relapse frequency and development of progressively aggressive cancers; developing new treatment options for PCa remains crucial. In this project, a series of synthetic compounds based on natural products will be screened to identify inhibitors for Aurora-A kinase (Aur-A). Aur-A facilitates centrosome separation and bipolar spindle formation during mitosis. Aur-A is overexpressed in metastatic PCa cells, and is a good candidate...
Show moreCurrent treatments for prostate cancer (PCa) are marred with high relapse frequency and development of progressively aggressive cancers; developing new treatment options for PCa remains crucial. In this project, a series of synthetic compounds based on natural products will be screened to identify inhibitors for Aurora-A kinase (Aur-A). Aur-A facilitates centrosome separation and bipolar spindle formation during mitosis. Aur-A is overexpressed in metastatic PCa cells, and is a good candidate for targeted therapies. Compound libraries are designed using natural compounds that contain simple structural elements as starting points for developing drug like libraries. High-throughput screening of these libraries will be used to identify potent antimitotic agents that selectively affect cancer cells but not normal cells. A combination of in vitro protein assays � quantifying protein activity � cell-based assays � measuring cell growth and proliferation � and cell-reporter assays � to determine which metabolic pathway the compound affects � were used to identify potential inhibitors. Through these methods, we have identified several compounds, with special consideration to thiazole piperazine compounds, to successfully inhibit proliferation of metastatic PCa cells.
Show less - Date Issued
- 2016
- Identifier
- CFH2000103, ucf:45549
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFH2000103
- Title
- The Role of LIM Kinase 1 and its Substrates in Cell Cycle Progression.
- Creator
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Ritchey, Lisa, Chakrabarti, Ratna, Zervos, Antonis, Zhao, Jihe, Vonkalm, Laurence, University of Central Florida
- Abstract / Description
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LIM Kinase 1 (LIMK1), a modulator of actin and microtubule dynamics, has been shown to be involved in cell cycle progression. In this study we examine the role of LIMK1 in G1 phase and mitosis. We found ectopic expression of LIMK1 resulted in altered expression of p27Kip1, the G1 phase Cyclin D1/Cdk4 inhibitor. Overexpression of LIMK1 resulted in lower levels of p27Kip1 and p27Kip1-pY88 (inactive p27Kip1). Knockdown of LIMK1 resulted in elevated levels of p27Kip1 and p27Kip1-pY88. Together,...
Show moreLIM Kinase 1 (LIMK1), a modulator of actin and microtubule dynamics, has been shown to be involved in cell cycle progression. In this study we examine the role of LIMK1 in G1 phase and mitosis. We found ectopic expression of LIMK1 resulted in altered expression of p27Kip1, the G1 phase Cyclin D1/Cdk4 inhibitor. Overexpression of LIMK1 resulted in lower levels of p27Kip1 and p27Kip1-pY88 (inactive p27Kip1). Knockdown of LIMK1 resulted in elevated levels of p27Kip1 and p27Kip1-pY88. Together, these results suggest LIMK1 regulates progression of G1 phase through modulation of p27Kip1 expression.LIMK1 is involved in the mitotic process through inactivating phosphorylation of Cofilin. Aurora kinase A (Aur-A), a mitotic kinase, regulates initiation of mitosis through centrosome separation and proper assembly of bipolar spindles. Phosphorylated LIMK1 is recruited to the centrosomes during early prophase, where it colocalizes with ?-tubulin. Here, we report a novel functional cooperativity between Aur-A and LIMK1 through mutual phosphorylation. LIMK1 is recruited to the centrosomes during early prophase and then to the spindle poles, where it colocalizes with Aur-A. Aur-A physically associates with LIMK1 and activates it through phosphorylation, which is important for its centrosomal and spindle pole localization. Aur-A also acts as a substrate of LIMK1, and the function of LIMK1 is important for its specific localization and regulation of spindle morphology. Taken together, the novel molecular interaction between these two kinases and their regulatory roles on one other's function may provide new insight on the role of Aur-A in manipulation of actin and microtubular structures during spindle formation.The substrates of LIMK1, Aur-A and Cofilin, are also involved in the mitotic process. Aur-A kinase regulates early mitotic events through phosphorylation and activation of a variety of proteins. Specifically, Aur-A is involved in centrosomal separation and formation of mitotic spindles in early prophase. The effect of Aur-A on mitotic spindles is mediated by modulation of microtubule dynamics and association with microtubule binding proteins. In this study we show that Aur-A exerts its effects on spindle organization through regulation of the actin cytoskeleton. Aur-A phosphorylates Cofilin at multiple sites including S3 resulting in inactivation of its actin depolymerizing function. Aur-A interacts with Cofilin in early mitotic phases and regulates its phosphorylation status. Cofilin phosphorylation follows a dynamic pattern during progression of prophase to metaphase. Inhibition of Aur-A activity altered subcellular localization of Cofilin and induced a delay in the progression of prophase to metaphase. Aur-A inhibitor also disturbed the pattern of Cofilin phosphorylation, which correlated with the mitotic delay. Our results establish a novel function of Aur-A in the early mitotic stage through regulation of actin cytoskeleton reorganization.?
Show less - Date Issued
- 2014
- Identifier
- CFE0005701, ucf:50156
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0005701