The long term objective of this research proposal is to seek a more complete understanding of the mechanisms through which extracellular signals regulate the growth and differentiation of skeletal muscle cells. Recent findings indicate that the differentiation process is under the control of a number of regulator genes. Enforced expression of these genes, even in normally nonmyogenic cell types, leads to the expression of differentiation markers. Available evidence suggests that these regulator genes may interact with other transcription factors to regulate muscle specific gene expression. Major advances have also been made in the field of signal transduction within the last five years. We and others have identified a set of primary response genes whose activation appears to be a critical step in several signal transduction pathways. Many of these primary response genes which include the protooncogenes c-fos and c-jun appear to be potential transcription factors. The apparent importance of the primary sponse genes in the muscle differentiation process is underscored by the observation that transformation of myogenic cells with c- fos inhibits their differentiation. The research program to be implemented during the grant period attempts to identify primary response genes that play a significant and specific role in regulating muscle differentiation and to define the mechanism(s) of their functional involvement. It will compare the expression and inducibility of these genes between proliferating myoblasts and differentiated myocytes to determine the molecular basis of the loss of mitogenic responsiveness following muscle differentiation. Knowledge gathered from this research should have intrinsic implications on the basic developmental echanisms regulating muscle cell growth and differentiation. In addition, the molecular basis of growth inhibition in terminally differentiated muscle cells might shed light on how antioncogenes might function in preventing tumorigenesis. Results from this project will also advance our understanding of the signal transduction systems that are employed under many biological contexts.
