The transforming v-rel gene-containing retrovirus causes multiple lymphomas in infected young chicken within 7-10 days. The v-rel oncogene and its cellular homologue, c-rel, belong to the Rel/NF-kappaB family proteins that control the transcription of many viral and cellular genes including HIV-l and lymphokines. The goal of the proposed research is (i) to identify novel c-Rel-interacting factors, and (ii) to characterize at the molecular level how mutations can alter dimerization spectrum and function of c-Rel. These specific questions will be addressed: l. How c-Rel transduces mitogenic signals? We will clone novel c-Rel- interacting factors by the expression cloning method or the two-hybrid system. The identities of these factors will provide insightful information about the molecules that transduce mitogenic signals to and from c-Rel. 2. What mutations change the dimerization spectrum of c-Rel? What dimerizations are important for c-Rel function? We will generate c-Rel mutant library by random mutagenesis. The two-hybrid system, a genetic method for detecting protein interactions, will be used to screen mutant library. We will identify the mutants that are defective in either homo- or hetero-dimerization. Transcriptional activities of these mutants will be examined to identify the protein interactions that are important for c- Rel action. 3. What signal transduction pathways require c-Rel? We will construct the dominant-negative mutants that specifically inhibit c-Rel function. They will be used to prove the c-Rel involvement in various T-cell activation pathways. In total, these studies will assess systematically the significance of different protein-protein interactions in c-Rel function. This will also provide parallel understanding of other Rel/NF-kappaB family of transcription factors. The information gained in these studies will be important in our understanding of signal transduction pathways and oncogenesis mediated by c-Rel. It also will be of value in the future design of therapeutic agents for AIDS and other immunological disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM049875-04
Application #
2187433
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1993-08-01
Project End
1998-07-31
Budget Start
1996-08-01
Budget End
1998-07-31
Support Year
4
Fiscal Year
1996
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Hu, M C; Tang-Oxley, Q; Qiu, W R et al. (1998) Protein phosphatase X interacts with c-Rel and stimulates c-Rel/nuclear factor kappaB activity. J Biol Chem 273:33561-5
Chen, Y R; Wang, W; Kong, A N et al. (1998) Molecular mechanisms of c-Jun N-terminal kinase-mediated apoptosis induced by anticarcinogenic isothiocyanates. J Biol Chem 273:1769-75
Oehrl, W; Kardinal, C; Ruf, S et al. (1998) The germinal center kinase (GCK)-related protein kinases HPK1 and KHS are candidates for highly selective signal transducers of Crk family adapter proteins. Oncogene 17:1893-901
Yu, R; Jiao, J J; Duh, J L et al. (1997) Activation of mitogen-activated protein kinases by green tea polyphenols: potential signaling pathways in the regulation of antioxidant-responsive element-mediated phase II enzyme gene expression. Carcinogenesis 18:451-6
Yu, R; Tan, T H; Kong, A T (1997) Butylated hydroxyanisole and its metabolite tert-butylhydroquinone differentially regulate mitogen-activated protein kinases. The role of oxidative stress in the activation of mitogen-activated protein kinases by phenolic antioxidants. J Biol Chem 272:28962-70
Diener, K; Wang, X S; Chen, C et al. (1997) Activation of the c-Jun N-terminal kinase pathway by a novel protein kinase related to human germinal center kinase. Proc Natl Acad Sci U S A 94:9687-92
Mayr, C A; Sami, S M; Dorr, R T (1997) In vitro cytotoxicity and DNA damage production in Chinese hamster ovary cells and topoisomerase II inhibition by 2-[2'-(dimethylamino)ethyl]-1, 2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones with substitutions at the 6 and 7 positions (azonafides). Anticancer Drugs 8:245-56
Wang, W; Zhou, G; Hu, M C et al. (1997) Activation of the hematopoietic progenitor kinase-1 (HPK1)-dependent, stress-activated c-Jun N-terminal kinase (JNK) pathway by transforming growth factor beta (TGF-beta)-activated kinase (TAK1), a kinase mediator of TGF beta signal transduction. J Biol Chem 272:22771-5
Chen, Y R; Wang, X; Templeton, D et al. (1996) The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma radiation. Duration of JNK activation may determine cell death and proliferation. J Biol Chem 271:31929-36
Hu, M C; Qiu, W R; Wang, X et al. (1996) Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade. Genes Dev 10:2251-64

Showing the most recent 10 out of 18 publications