Abstract

The overall goal of this application is to elucidate mechanisms of growth regulation to understand the processes that lead to proliferative disorders. Growth factors have been demonstrated to control growth through their actions on G1 cell cycle specific proteins which, in turn, control the actions of tumor suppressor genes. It is imperative to understand the regulation of D-type cyclin activities and their effects on specific growth suppressive pathways. This objective will be accomplished through the following specific aims:
Aim 1 will determine the substrate specificity of each cyclin D/cdk4 complex towards Rb family member proteins.
Aim 2 will determine the mechanism of ternary cyclin D/cdk4/p27kip1 or cyclin D/cdk4/p21cip1 complex formation and the dynamics of addition of newly synthesized subunits to, and concomitant loss of, old subunits from such complexes, and how such alterations modulate cdk activity and substrate specificity.
Aim 3 will determine the mechanism of activation of cdk4 activation, i.e. identify the steps required to generate catalytically active enzyme in vivo after complex formation with a cyclin D partner.
Aim 4 will identify the regions of each D-type cyclin responsible for its interaction with cdk4.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA067360-09
Application #
6512879
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Spalholz, Barbara A
Project Start
1994-09-30
Project End
2003-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
9
Fiscal Year
2002
Total Cost
$252,221
Indirect Cost

  Institution

Name
University of South Florida
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Tampa
State
FL
Country
United States
Zip Code
33612

  Publications

Bagui, Tapan K; Cui, Dongming; Roy, Sangita et al. (2009) Inhibition of p27Kip1 gene transcription by mitogens. Cell Cycle 8:115-24
Mohapatra, Subhra; Chu, Baoky; Zhao, Xiuhua et al. (2009) Apoptosis of metastatic prostate cancer cells by a combination of cyclin-dependent kinase and AKT inhibitors. Int J Biochem Cell Biol 41:595-602
Roy, Sangita; Shor, Audrey C; Bagui, Tapan K et al. (2008) Histone deacetylase 5 represses the transcription of cyclin D3. J Cell Biochem 104:2143-54
Engelman, Robert W; Jackson, Rosalind J; Coppola, Domenico et al. (2007) Loss of nuclear p21(Cip1/WAF1) during neoplastic progression to metastasis in gamma-irradiated p21 hemizygous mice. Exp Mol Pathol 82:234-44
Shor, Audrey C; Keschman, Elizabeth A; Lee, Francis Y et al. (2007) Dasatinib inhibits migration and invasion in diverse human sarcoma cell lines and induces apoptosis in bone sarcoma cells dependent on SRC kinase for survival. Cancer Res 67:2800-8
Jackson, Rosalind J; Engelman, Robert W; Coppola, Domenico et al. (2003) p21Cip1 nullizygosity increases tumor metastasis in irradiated mice. Cancer Res 63:3021-5
Bagui, Tapan K; Mohapatra, Subhra; Haura, Eric et al. (2003) P27Kip1 and p21Cip1 are not required for the formation of active D cyclin-cdk4 complexes. Mol Cell Biol 23:7285-90
Jackson, Rosalind J; Adnane, Jalila; Coppola, Domenico et al. (2002) Loss of the cell cycle inhibitors p21(Cip1) and p27(Kip1) enhances tumorigenesis in knockout mouse models. Oncogene 21:8486-97
Mohapatra, S; Agrawal, D; Pledger, W J (2001) p27Kip1 regulates T cell proliferation. J Biol Chem 276:21976-83
Bowman, T; Broome, M A; Sinibaldi, D et al. (2001) Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc Natl Acad Sci U S A 98:7319-24

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