St Vincent's Institute

• Research units

• Structural Biology
• Protein Chemistry and Metabolism
• Molecular Cardiology
• Immunology and Diabetes
• Bone Cell Biology and Disease
• Stem Cell Regulation
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• Molecular Genetics
• Cell Cycle and Cancer
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• Cytoskeleton and Cancer
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• Genome Stability

Regulation of growth factor signaling and cell cycle progression

Project Type

PhD

Summary

Significant evidence indicates that the chromatin-remodelling SWI/SNF complexes play an important role in regulating cell proliferation by regulating transcription and potentially, DNA replication. Recent studies form our laboratory and collaborators at the Peter MacCallum Cancer Centre demonstrate that the Brahma SWI/SNF complex controls the Ras/Mek/MAPK signaling pathway, a fundamental pathway in eukaryotes which controls proliferation and differentiation. The finetuning of signal strength and duration of the Ras/Mek/Erk pathway is important in controlling cell fate determination. For example, transient activation of this pathway can induce cell proliferation, while sustained activation can induce differentiation. In addition, the aberrant activation of this pathway is a common feature in many human cancers. This project will define how Brahma controls signaling through the Ras/Mek/Erk pathway.

A second aspect of this project involves analysis of the effects of cyclin E/CDK2-mediated phosphorylation of Brahma in controlling G1-S phase cell cycle progression. Evidence from the laboratory suggests that cyclin E/CDK2 phosphorylates Brahma to promote cell cycle progression. Studies will be performed to determine if the wild-type and phosphorylation site mutants of Brahma have differential effects on regulating cell division and their chromatin remodelling activity or DNA replication. These studies will be complemented by genetic studies in Drosophila melanogaster to evaluate the role of Brahma in a whole organism by evaluating phenotypes associated with cell proliferation such as rough eye, altered wing notching and wing vein truncation. Transgenic flies have already been generated and interesting novel data obtained. Brahma SWI/SNF subunits are mutated in human cancer and function as tumour suppressors. This research will determine if the SWI/SNF tumour suppressor complex is a critical downstream target of cyclin E/CDK2. This work will also increase our understanding of how cyclin E regulates cell cycle transitions and how it can behave as an oncogene when overexpressed in human cancer.

Supervisor: Dr Boris Sarcevic