The Role of CDKs in Normal and Neoplastic Proliferation

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Title: The Role of CDKs in Normal and Neoplastic Proliferation
Author: Macias, Everardo Macias
Advisors: Robert Smart, Committee Member
Marcelo Rodriguez-Puebla, Committee Co-Chair
John Cullen, Committee Member
Jonathan Horowitz, Committee Co-Chair
Abstract: Cyclin-dependant kinases (CDKs) are serine/threonine kinases which play a central role in cell cycle progression. The more characterized function of CDKs is the phosphorylation and inhibition of pRb allowing the transcription of genes needed for cell cycle progression from G1 to S phase. Loss or mutation of pRb results in deregulated cell growth however; this is also achieved by functional inactivation due to elevated CDK activity. In particular, molecular analysis of some human tumors shows deregulated CDK2 and CDK4 activity. CDK4 is implicated in tumor development since it is frequently found overexpressed, genetically amplified and mutated in human tumors. In contrast, CDK2 is not mutated and is rarely found genetically amplified or overexpressed. Therefore, it remains unclear whether elevated CDK2 kinase activity in human tumors is a causative effect or consequence of the disease. The general purpose of our studies has been to determine the role CDK2 and CDK4 in normal and neoplastic proliferation. In order to investigate the role of CDK2 in tumorigenesis we developed two transgenic mouse models of elevated CDK2 kinase activity. Here we report that elevated CDK2 kinase activity per se does not enhance tumorigenesis in the mouse skin or pituitary gland. In addition, we have established that CDK2 is necessary for h-Ras/CDK4-induced tumors, but is dispensable for myc-induced tumorigenesis. Thus, CDK2 is necessary, but not sufficient to induce tumor development. These results suggest that the efficacy of using CDK2 inhibitors will depend on the oncogenic pathway involved. We have also provided insights into mechanisms that are unique to CDK4 kinase activity. We report that overexpression of CDK4 can alter cell fate of pituitary progenitor cells, which collaborates with an additional hit to promote the early onset and progression of pituitary tumors. Additionally, we demonstrate that overexpression of CDK4 alters TGF-β signaling via phosphorylation of Smad2/3, suggesting that in conjunction to pRb CDK4 regulates additional pathways. Whether regulation of cell fate and TGF-β signaling by CDK4 is a prominent event in tumorigenesis will have significant translational implications.
Date: 2008-12-04
Degree: PhD
Discipline: Comparative Biomedical Sciences

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