MOLECULAR MECHANISMS OF TRANSFORMATION BY AP-1 PROTEINS

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DESCRIPTION: (adapted from the investigator's abstract) 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.