Carcinogenesis is caused by multiple co-operating genetic lesions leading to a progressive deregulation of cellular signaling and cell cycle restriction point control. The mutations involved result in oncogene activation or loss of tumor-suppressor gene function. However, the mechanisms by which these mutant genes co-operate in malignant cell transformation are largely unknown. Our laboratory has shown that the co-operation of oncogenic lesions involves integration of multiple signals converging on the regulation of cell cycle-dependent kinase complexes. Here we propose to investigate the molecular mechanisms by which the c-myc oncogene co-operates with activated Ras/Raf signaling. The c-myc oncogene is frequently activated in human cancer and is a potent inducer of proliferation and apoptosis. One essential step in Myc-induced proliferation is the activation of Cyclin E-dependent kinase (Cyclin E/Cdk2). Using genetic and biochemical approaches in tissue culture, we recently made the surprising finding that activation of cyclin E/Cdk2 by c-myc requires the ability of D cyclins to sequester Gl cell cycle inhibitors p27Kip1 and p21Cip1 (Ckis). We now propose to investigate whether the capability of D cyclins to sequester Ckis plays an important role in the induction of cell division by activated c-myc in an intact organism. Moreover, we plan to tea the hypothesis that sequestration of Ckis by D cyclins may play a significant role in organ development and during multi-step carcinogenesis. This work will provide insight into developing signaling pathway-based strategies for cancer therapy in humans.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA090663-01
Application #
6321822
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Spalholz, Barbara A
Project Start
2001-03-01
Project End
2006-02-28
Budget Start
2001-03-01
Budget End
2002-02-28
Support Year
1
Fiscal Year
2001
Total Cost
$330,963
Indirect Cost
Name
University of Rochester
Department
Genetics
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
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