The goal of this program is to further our understanding of the mechanisms that regulate the progression of cells from the G1 phase to the S phase of the cell cycle and to determine how specific oncoproteins (i.e. mutant CDK4, E1A and MDM2) and potential tumor suppressor proteins (p130 and p107) alter these critical regulatory pathways. In Project #1, Dr. Reddy, utilizing a transgenic mouse model system, plans to determine how a tumor-derived mutation in the cyclin-dependent kinase 4 (CDK4) alters G1 to S progression and mediates escape from cellular senescence in vitro and promotes tumorigenesis in vivo. In Project #2, Dr.
Grana aims to define p130 phosphorylation events that occur as cells pass through late G1 and S phases of the cell cycle that appear to regulate p130 protein stability, the mechanisms that result in p130 depletion, and the biological significance of these events in senescence and transformation. Finally, in Project 3, Dr. Haines plans to characterize how the novel cell cycle control molecule MTBP regulates G1 to S progression and how the MDM2 oncoprotein negatively affects MTBP function. The program is also logistically supported by three Cores; a Transgenic Animal Core (A), a Virology/Cell Culture Core (B) and an Administrative Core (C). The cores will be essential for the successful completion of all research projects. The studies proposed under this Program Project should provide the scientific community with a better understanding of the mechanisms that regulate G1/S progression in mammalian cells and how activation of particular oncogenes alone or in combination with inactivation of tumor suppressor genes from this pathway leads to tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA095569-05
Application #
7171831
Study Section
Subcommittee G - Education (NCI)
Program Officer
Spalholz, Barbara A
Project Start
2003-02-14
Project End
2009-01-31
Budget Start
2007-02-01
Budget End
2009-01-31
Support Year
5
Fiscal Year
2007
Total Cost
$1,267,414
Indirect Cost
Name
Temple University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Reddy, Haritha K D L; Grana, Xavier; Dhanasekaran, Danny N et al. (2010) Requirement of Cdk4 for v-H-ras Induced Breast Tumorigenesis and Activation of the v-ras-induced Senescence Program by the R24C mutation. Genes Cancer 1:69-80
Jayadeva, Girish; Kurimchak, Alison; Garriga, Judit et al. (2010) B55alpha PP2A holoenzymes modulate the phosphorylation status of the retinoblastoma-related protein p107 and its activation. J Biol Chem 285:29863-73
Garriga, Judit; Xie, Hongbo; Obradovic, Zoran et al. (2010) Selective control of gene expression by CDK9 in human cells. J Cell Physiol 222:200-8
Odvody, J; Vincent, T; Arrate, M P et al. (2010) A deficiency in Mdm2 binding protein inhibits Myc-induced B-cell proliferation and lymphomagenesis. Oncogene 29:3287-96
Chawla, Rachna; Procknow, Judith A; Tantravahi, Ramana V et al. (2010) Cooperativity of Cdk4R24C and Ras in melanoma development. Cell Cycle 9:3305-14
Abedin, Zahidur R; Ma, Zhongjie; Reddy, E Premkumar (2010) Increased angiogenesis in Cdk4(R24C/R24C):Apc(+/Min) intestinal tumors. Cell Cycle 9:2456-63
Mtango, Namdori R; Potireddy, Santhi; Latham, Keith E (2009) Expression of microRNA processing machinery genes in rhesus monkey oocytes and embryos of different developmental potentials. Mol Reprod Dev 76:255-69
Sotillo, Elena; Garriga, Judit; Padgaonkar, Amol et al. (2009) Coordinated activation of the origin licensing factor CDC6 and CDK2 in resting human fibroblasts expressing SV40 small T antigen and cyclin E. J Biol Chem 284:14126-35
Grana, Xavier (2008) Downregulation of the phosphatase nuclear targeting subunit (PNUTS) triggers pRB dephosphorylation and apoptosis in pRB positive tumor cell lines. Cancer Biol Ther 7:842-4
Mtango, N R; Harvey, A J; Latham, K E et al. (2008) Molecular control of mitochondrial function in developing rhesus monkey oocytes and preimplantation-stage embryos. Reprod Fertil Dev 20:846-59

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