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Webinars - Cancer

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VHL-mediated ubiquitination of the kinase Mps1 regulates the mitotic checkpoint in clear cell renal cell carcinoma

Abnormal chromosome segregation during mitosis causes aneuploidy, a hallmark of cancers associated with high risk for tumorigenesis, which is normally regulated by the mitotic checkpoint. Mps1 kinase activity is essential for spindle checkpoint signaling. Mps1 is over-expressed in clear cell renal cell carcinoma (ccRCC) and requires the molecular chaperone Hsp90 for its activity. Mps1 phosphorylates Hsp90, regulating chaperone function of numerous oncogenic client proteins, including Mps1, and conferring tumor selectivity of Hsp90 inhibitors in ccRCC. The most frequent alteration leading to ccRCC is loss of von Hippel Lindau (VHL), the recognition subunit of an E3-ubiquitin ligase complex that targets proteins for degradation. As Mps1 is over-expressed in ccRCC, the objective of the current study was to determine whether Mps1 gets targeted for degradation by VHL and whether this regulates the mitotic checkpoint. Mps1 kinase is ubiquitinated by a VHL containing E3-ubiquitin ligase complex and Mps1 activity is essential for its ubiquitination. Re-expression of VHL in VHL-null ccRCC cell lines leads to proteasomal degradation of Mps1. VHL degrades Mps1 in an oxygen independent manner by ubiquitination of Mps1-K86, K827, and K848. Mps1 ubiquitination regulates cell cycle progression via exit from the mitotic checkpoint. Mps1 is targeted for degradation by the tumor suppressor VHL in a hypoxia-independent manner and Mps1 is over-expressed in VHL-null ccRCC. VHL-mediated ubiquitination of Mps1 regulates mitotic checkpoint progression. Mps1 stability additionally mediates Hsp90 post-translational modification and tumor selectivity of Hsp90 inhibitors.

Summary: Cell cycle dysregulation is a common driver of tumorigenesis. In clear cell renal cell carcinoma (ccRCC), the mitotic checkpoint is disrupted via the loss of the E3 ubiquitin ligase complex subunit VHL which contributes to over expression of Mps1 and disrupted cell cycle exit from the mitotic checkpoint. Therefore, VHL-mediated ubiquitination of Mps1 regulates mitotic checkpoint progression. Further, Mps1 stability additionally mediates Hsp90 post-translational modification and effectiveness of Hsp90 inhibitors in treating cancer, providing insight for future treatment options for ccRCC.

Main Target Audience: Anyone studying the cell cycle, ubiquitination, protein folding, chaperones, cancer, post translational modifications, mitosis. Likely academic scientists.

Why should you attend?: In this webinar, Dr. Woodford will explain vital aspects of the cell cycle and how disruptions result in cancer. You will learn about the relationship between protein expression, modification, and degradation and how they regulate the mitotic checkpoint. You will also learn how this fascinating biological relationship can be exploited to develop successful cancer treatments.

Presented by: Dr. Mark Woodford, PhD
Assistant professor
Department of Urology, SUNY Upstate Medical University

Topic: Cancer



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