Abstract

The goal of this proposal is to further characterize IL-3 signal transduction with focus on activation of RAF-1, which leads to hematopoietic proliferation, and BCL-2-alpha which leads to inhibition of apoptosis. There are two specific aims.
Specific Aim 1 is to determine the mechanism and functional significance of IL-3 mediated phosphorylation and activation of RAF-1.
Sub aims will be to determine if protein kinase C-alpha is the direct activator of RAF-1, to determine which sites on RAF-1 which are phosphorylated are important for activation, to determine the role of IL-3 mediated RAF-1 tyrosine phosphorylation and to determine how RAF-1 is activated in the complex with MEK. The second specific aim is to determine the mechanism, site, and functional significance of IL-3 induced BCL-2 phosphorylation.
Sub aims are to determine whether PKC-alpha phosphorylates BCL-2 alpha directly, to determine how phosphorylation affects BCL-2 function, and to determine whether RAF-1 and the BCL-2 interact, and if BCL-2 is a target of RAF-1.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA044649-07A2
Application #
2091540
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1991-04-01
Project End
1998-08-31
Budget Start
1995-09-19
Budget End
1996-08-31
Support Year
7
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

Name
University of Texas Medical Br Galveston
Department
Type
Organized Research Units
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555

  Publications

Yang, Mingli; Wu, Song; Jia, Jinghua et al. (2011) JAZ mediates G1 cell cycle arrest by interacting with and inhibiting E2F1. Cell Cycle 10:2390-9
May, William Stratford; Hoare, Kishalay; Hoare, Sarasija et al. (2010) Tnk1/Kos1: a novel tumor suppressor. Trans Am Clin Climatol Assoc 121:281-92; discussion 292-3
Deng, Xingming; Gao, Fengqin; May, W Stratford (2009) Protein phosphatase 2A inactivates Bcl2's antiapoptotic function by dephosphorylation and up-regulation of Bcl2-p53 binding. Blood 113:422-8
Hoare, Sarasija; Hoare, Kishalay; Reinhard, Mary K et al. (2009) Functional characterization of the murine Tnk1 promoter. Gene 444:1-9
Cao, Xuefang; Bennett, Richard L; May, W Stratford (2008) c-Myc and caspase-2 are involved in activating Bax during cytotoxic drug-induced apoptosis. J Biol Chem 283:14490-6
Wang, Yan-Yi; Deng, Xingming; Xu, Lijun et al. (2008) Bcl2 enhances induced hematopoietic differentiation of murine embryonic stem cells. Exp Hematol 36:128-39
Yang, Mingli; Wu, Song; Su, Xuekun et al. (2006) JAZ mediates G1 cell-cycle arrest and apoptosis by positively regulating p53 transcriptional activity. Blood 108:4136-45
Deng, Xingming; Gao, Fengqin; Flagg, Tammy et al. (2006) Bcl2's flexible loop domain regulates p53 binding and survival. Mol Cell Biol 26:4421-34
Deng, Xingming; Gao, Fengqin; Flagg, Tammy et al. (2004) Mono- and multisite phosphorylation enhances Bcl2's antiapoptotic function and inhibition of cell cycle entry functions. Proc Natl Acad Sci U S A 101:153-8
Varma, Tushar; Liu, Si Qi; West, Matthew et al. (2003) Protein kinase C-dependent phosphorylation and mitochondrial translocation of aldose reductase. FEBS Lett 534:175-9

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