REGULATION OF CELL PROLIFERATION

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DESCRIPTION (adapted from the applicant's abstract): The cytoskeletal beta- and gamma-actin genes encode the principal structural proteins of cellular microfilaments and are members of a diverse class of growth factor-regulated genes termed cellular "immediate early" (IE) genes. While the salient feature of these genes is their rapid transcriptional activation in response to proliferation stimuli, muscle-specific actin genes are generally expressed only during terminal differentiation of cells of myogenic lineage. An exception to this rule, however, is the vascular smooth muscle (VSM) alpha-actin gene which, in addition to activation during smooth muscle cell differentiation, is also expressed in stromal "myofibroblasts"-specialized cell types associated with proliferative responses to growth factors, cytokines, and inflammatory stimuli. Consistent with a role in cell proliferation, the applicant has recently shown that the VSM-actin promoter has the potential to be expressed as a cellular IE gene in serum-stimulated fibroblasts in culture. The applicant now proposes to test the hypothesis that cell- type-specific transcriptional repression mechanisms are responsible, in part, for the differential patterns of VSM alpha-actin expression in myogenic cells and in fibroblasts. Specifically, the applicant postulates that silencing in fibroblasts results from interference with the ability of transcriptional enhancer factor 1 (TEF-1), or a closely related protein, to synergistically activate VSM alpha-actin transcription. Moreover, the applicant proposes a mechanism mediated by recently identified single-stranded DNA (ssDNA) binding proteins. In undifferentiated myoblasts, however, site- directed mutagenesis studies clearly indicate that the mechanisms which repress VSM alpha- actin transcription differ.