Molecular, genetic, and biochemical characterization has demonstrated that the transcription factor AP-1, which is composed of dimeric complexes of Fos and Jun proteins, regulates cellular responses to diverse extracellular stimuli. AP-1 participates in the conversion of cells from normal to malignant growth in at least two separate contexts. First, genes of the Fos and Jun family can serve as the primary targets of mutational activation, as in the case of Fos and Jun containing oncogenic retroviruses. In addition, AP-1 proteins can function as effectors of transformation by several different cytoplasmic oncoproteins, many of which are common targets of mutational activation in human cancers. In addition to playing a role in mediating transformation, they have shown by genetic analysis that AP-1 proteins in general, and c-Jun in particular, play important roles in two cellular processes that may be related to the ability to effect oncogenic changes: in fibroblasts, c-Jun is required for normal cell cycle progression and protects cells from apoptosis in response to two different apoptotic stimuli, U/V irradiation and the cytokine TNF. Their long term goal is to understand in molecular detail the normal functions of AP-1 proteins and how deregulation of this transcription factor contributes to the development of cancer. To reach this goal, they propose experiments to address the following questions: 1) role does phosphorylation of FosB protein (and Fos proteins in general) play in the regulation of transcriptional activation and neoplastic transformation? 2) What are the kinases that mediate phosphorylation at functionally important sites, and how are they regulated? 3) What is the role of c-Jun, JNK, and the JNK/cJun interaction in the control of neoplastic transformation, cell proliferation, and apoptosis? 4) How is the AP-1 responsiveness of the cyclin D1 promoter regulated so that it is not induced by anti-proliferative stimuli that activate AP-1, such as U/V irradiation? They propose a series of genetic, biochemical, and cell biologic experiments to address these issues. The answers to these questions will increase our understanding of the molecular basis of transformation by AP-1.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA064118-08
Application #
6497724
Study Section
Pathology B Study Section (PTHB)
Program Officer
Perry, Mary Ellen
Project Start
1995-04-03
Project End
2004-01-31
Budget Start
2002-02-01
Budget End
2004-01-31
Support Year
8
Fiscal Year
2002
Total Cost
$265,110
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Kim, Sungeun; Denny, Christopher T; Wisdom, Ron (2006) Cooperative DNA binding with AP-1 proteins is required for transformation by EWS-Ets fusion proteins. Mol Cell Biol 26:2467-78
Sprowles, Amy; Robinson, Dan; Wu, Yi-Mi et al. (2005) c-Jun controls the efficiency of MAP kinase signaling by transcriptional repression of MAP kinase phosphatases. Exp Cell Res 308:459-68
Wisdom, Ron; Huynh, Lyanne; Hsia, Datsun et al. (2005) RAS and TGF-beta exert antagonistic effects on extracellular matrix gene expression and fibroblast transformation. Oncogene 24:7043-54
Sprowles, Amy; Wisdom, Ron (2003) Oncogenic effect of delta deletion in v-Jun does not result from uncoupling Jun from JNK signaling. Oncogene 22:498-506
Qu, S; Tucker, S C; Zhao, Q et al. (1999) Physical and genetic interactions between Alx4 and Cart1. Development 126:359-69
Tucker, S C; Wisdom, R (1999) Site-specific heterodimerization by paired class homeodomain proteins mediates selective transcriptional responses. J Biol Chem 274:32325-32
Wisdom, R; Johnson, R S; Moore, C (1999) c-Jun regulates cell cycle progression and apoptosis by distinct mechanisms. EMBO J 18:188-97
Qu, S; Tucker, S C; Ehrlich, J S et al. (1998) Mutations in mouse Aristaless-like4 cause Strong's luxoid polydactyly. Development 125:2711-21
Skinner, M; Qu, S; Moore, C et al. (1997) Transcriptional activation and transformation by FosB protein require phosphorylation of the carboxyl-terminal activation domain. Mol Cell Biol 17:2372-80
Qu, S; Li, L; Wisdom, R (1997) Alx-4: cDNA cloning and characterization of a novel paired-type homeodomain protein. Gene 203:217-23

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