Ron M. Prywes
Growth Factors and OncogenesOncogenes have been isolated from human or animal tumors by their ability to cause a cancerous or "transformed" phenotype when introduced into certain nontransformed cell lines. These genes are altered versions of cellular genes, proto-oncogenes, that play roles in normal cellular growth and differentiation. I have been interested in understanding the mechanism of action of oncogenes and proto-oncogenes both in oncogenesis and in normal cellular growth control.
Oncogenes fall into several classes depending upon the func tion and localization of their protein products. There are proto-oncogenes that code for secreted growth factors, cell sur face receptors, cytoplasmic protein kinases, and nuclear tran scription factors. Each of these protein is involved in at least one step in the complex pathways of cellular growth control. It is as yet unclear how these and other steps might be related.
I have been approaching this problem by studying the regula tion of a nuclear oncogene, fos. Transcription of the c-fos gene is activated rapidly (within five minutes) in response to various growth factors and other agents that regulate the cell cycle. The increase in c-fos protein levels is involved in the subse quent transcriptional regulation of other genes involved in growth and differentiation. By studying the transcriptional re gulation of c-fos, I hope to trace a pathway of nuclear and cyto plasmic events that are activated by cell surface signals.
Mutational analysis of the c-fos promoter has identified a sequence element that can mediate a serum-or growth factor induced increase in transcription. A nuclear protein called serum response factor, or SRF, which binds to this element, has been purified and cloned.
A major focus of the laboratory is to understand how growth factors induce c-fos transcription through SRF. We have deter mined the region of SRF required for regulation in vivo and are now characterizing protein which complex with this region. These SRF-complexing proteins are likely to be critical for regulation of transactivation by SRF.
Another focus of the lab has been to determine how SRF and other transcription factors activate transcription. We have dissected the system in vitro and found that SRF interacts with the general transcription factor TFIIF. We are further charac terizing this novel interaction. We hope that the above studies will lead to a detailed understanding of how SRF regulates c-fos transcription and how cellular signaling pathways control SRF function.