The stimulation of cell proliferation by peptide growth factors is associated with the rapid transcriptional activation of a specific set of genes termed """"""""competence,"""""""" """"""""immediate-early,"""""""" pr """"""""early-response"""""""" genes. Alterations in the protein products of at least some of these genes and/or in the mechanisms by which they are regulated are believed to be central to both the acquisition and the progression of the transformed phenotype. This research will focus exclusively on the regulation of one such gene, that encoding cytoskeletal beta-actin, and will test two major hypotheses. First, it is proposed that negative regulation of transcription plays a key role in modulating beta-actin expression in growth factor stimulated cells, and secondly, that lesions in negative control mechanisms are responsible for altered patterns of beta-actin expression in at least one chemically-transformed cell line. These and alternate possibilities will be tested by delineating cis-acting regulatory elements and their cognate proteins which mediate the transcriptional response of the beta-actin gene to peptide growth factors in nontransformed AKR-2B mouse fibroblasts and in a 3-methylcholanthrene- transformed clonal derivative. The results of these studies will provide insight into the complex mechanisms by which peptide growth factors regulate specific gene expression and may provide information relevant to proposed models for multi-stage carcinogenesis and tumor suppression.
