University of Cambridge > > Cambridge Oncology Seminar Series > Signalling Networks in Cell Proliferation and Fate Control

Signalling Networks in Cell Proliferation and Fate Control

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If you have a question about this talk, please contact Dr Ireena Dutta.

Hutchison/MRC Research Centre Seminar

Control of cell division is a prerequisite for the precise formation of organs and body organization during embryonic development as well as tissue renewal and tissue maintenance thereafter. A defect in this control is elementary to the development of cancer and found in cancer cells of all cancer types. Because of such defects cancer cells enter division independent of external control and remain proliferation active under conditions where normal cells are unable, or cease, to divide. Loss of division control is critically important for the ability of cancers to expand at their primary site as well as for the ability of cancer metastasis to establish following spreading of individual cancer cells to remote tissues. We are trying to understand the molecular machinery required for cells to enter the cell division cycle and the mechanisms that leads cells to cease division activity transiently and terminally. The decision whether to enter cell division arises in the GAP1 (G1) phase of the cell cycle and normally required stimuli from the external environment. Key components controlling exit from G1 and onset of S phase are the cyclin D-dependent kinases CDK4 and CDK6 , and the cyclin E-associated kinase CDK2 , which phosphorylate and through this inactivate the retinoblastoma tumour suppressor protein (RB1). Genetic alterations that weaken or disable G1 checkpoint control are extremely frequent in cancers and presumed to promote cancer development by permitting unlicensed proliferation. Conversely, G1 checkpoint activation ensues in response to stress, including genotoxic insult and in such contexts is thought to provide resistance to therapy- and cancer inherent adversities. Although the key components of G1 checkpoint execution are recognised our understanding how G1 inherent signalling and stresses operate to modulate checkpoint function is far from complete. We developed a high throughput assay format allowing quantification of the phosphorylated, inactive form of RB1 in fixed cells seeded in a 96 well format. This assay in combination with targeted knockdown using siRNA libraries is identifying known and unexpected signalling required for checkpoint modulation in the different contexts. Results from these screens and their implications will be discussed.

This talk is part of the Cambridge Oncology Seminar Series series.

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