The Role of CDKs in Normal and Neoplastic Proliferation

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dc.contributor.advisor Robert Smart, Committee Member en_US
dc.contributor.advisor Marcelo Rodriguez-Puebla, Committee Co-Chair en_US
dc.contributor.advisor John Cullen, Committee Member en_US
dc.contributor.advisor Jonathan Horowitz, Committee Co-Chair en_US Macias, Everardo Macias en_US 2010-04-02T19:23:56Z 2010-04-02T19:23:56Z 2008-12-04 en_US
dc.identifier.other etd-08082007-215157 en_US
dc.description.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. en_US
dc.rights I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dis sertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to NC State University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. en_US
dc.subject pituitary en_US
dc.subject Ras en_US
dc.subject keratinocytes en_US
dc.subject CDK2 en_US
dc.subject c-Myc en_US
dc.subject Cell Cycle en_US
dc.subject Carcinogenesis en_US
dc.subject CDK4 en_US
dc.title The Role of CDKs in Normal and Neoplastic Proliferation en_US PhD en_US dissertation en_US Comparative Biomedical Sciences en_US

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