The Fos and Jun gene families encode a series of proteins that are components of the transcription factor AP-1. The oncogenic potential of this transcription factor is exemplified by the fact that both gene families were originally identified by their presence in the genomes of tumorigenic retroviruses. The Fos-Jun complex is a downstream component of a signal transduction pathway that includes the oncogenic tyrosine kinases and ras oncogenes, and AP-1 activity is induced by events that activate tyrosine kinase or ras activity. Therefore, it seems likely that an understanding of the molecular mechanisms involved in neoplastic transformation by AP-l proteins will also help clarify the events that underlie malignant transformation by these other oncoproteins. Although progress in understanding the molecular mechanisms involved in tumor formation by Fos and Jun proteins has been achieved, several critical questions remain unanswered. Our long term goal is to understand in molecular detail the normal functions of AP-l proteins and how deregulation of this transcription factor contributes to the development of cancer. To reach this goal, we propose specific aims to address the following questions: l) what are the proteins that determine the ability of Fos proteins to activate transcription? Fos family proteins contain a carboxyl-terminal activation domain that is required for transformation. We propose to carry out a mutational analysis to identify critical residues and secondary structures required for function of this domain. This will lead to strategies to identify proteins that interact with this domain and by doing so modulate its function. 2) What is the role of Jun proteins in transformation by Ras proteins? Jun proteins are hypothesized to function as critical mediators of the cellular transforming response to ras. We propose to test this hypothesis genetically, using cells containing null mutations at the c-Jun locus. 3) What are the functional domains required for transformation by AP-1? We will use AP-l proteins with altered dimerization specificity to determine the molecular and biochemical functions required for transformation by AP-l proteins. In addition, we will address non-AP-l determinants of transformation by AP-l proteins.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Pathology B Study Section (PTHB)
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Vanderbilt University Medical Center
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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
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; 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
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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