Ron Prywes

Oncogenes 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 function and localization of their protein products. There are proto-oncogenes that code for secreted growth factors, cell surface receptors, cytoplasmic protein kinases, and nuclear transcription 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.

We have been approaching this problem by studying the regulation of two nuclear oncogenes, c-fos and c-jun, whose transcription is rapidly activated by growth factors. The increase in fos and jun protein levels is involved in the subsequent transcriptional regulation of other genes involved in growth and differentiation. By studying the transcriptional regulation of fos and jun, we hope to trace a pathway of nuclear and cytoplasmic events that are activated by cell surface signals. Serum or growth factor induction of the c-fos promoter is mediated by the Serum Response Element (SRE). We have worked extensively on the main nuclear factor, SRF, that binds this element. A major focus of the laboratory is to understand how growth factors induce c-fos transcription through SRF. One set of pathways utilizing MAPK family members has been described, but mutational analysis of the SRE has shown that other pathways are critical for serum induction. These pathways include the small GTPases rho and rac as well as phosphatidyl inositol 3-kinase. We are further characterizing these pathways by identifying proteins which bind directly to SRF.

We are also further characterizing the role and regulation of a basic-leucine zipper (bZIP) transcription factor, ATF6, which we identified as binding SRF. ATF6 has also become quite interesting because it appears to have a key role in the "unfolded protein" stress response. ATF6 is a transmembrane protein located in the endoplasmic reticulum. Upon unfolded protein stress induction it is cleaved, releasing the cytoplasmic domain, thus allowing it to move to the nucleus and activate transcription. We are characterizing how this activation of ATF6 is regulated.

The regulation of the c-jun promoter is somewhat more complex in that at least two sequence elements are involved which bind the factors ATF-1 and MEF2D. MEF2D is particularly surprising since it is related to SRF in its DNA binding domain, suggesting that there could be a common mechanism of regulation. We have partially characterized the signalling pathways leading to these factors as involving ras, rac and the protein kinase MEKK. We are currently investigating how ATF-1 and MEF2D are directly regulated by this pathway.

Shen, J., Chen, X., Hendershot, L. and Prywes, R. (2002). ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev. Cell 3, 99-111. Abstract

Chen, X., Shen, J. and Prywes, R. (2002). The lumenal domain of ATF6 senses ER stress and causes translocation of ATF6 from the ER to the Golgi. J. Biol. Chem. 277(15):13045-52. Abstract

Wang Y, Shen J, Arenzana N, Tirasophon W, Kaufman RJ and Prywes R. (2000) Activation of ATF6 and an ATF6 DNA binding site by the ER stress response. J. Biol. Chem. 275(35): 27013-27020. Abstract

Ye J, Raswson RB, Komuro R, Chen X, Dave UP, Prywes R, Brown MS and Goldstein JL. (2000) ER Stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Molecular Cell 6, 1355-1364. Abstract

Wang Y and Prywes R. (2000) Activation of the c-fos enhancer by the Erk MAP kinase pathway through two sequence elements: the c-fos AP-1 and p62TCF sites. Oncogene 19, 1379-1385. Abstract

Chen X and Prywes R. (1999) Serum-induced expression of the cdc25A gene by relief of E2F-mediated repression. Mol Cell Biol 19, 4695-4702. Abstract

Wang, Y., Falasca, M., Schlessinger, J., Malstron, S., Tsichlis, P., Settleman, J., Lim, B., Prywes, R., (1998). Activation of the c-fos serum response element by phosphatidyl inositol 3-kinase and rho pathways. Cell Growth and Differentiation, 9:513-522 . Abstract

Clark, N., Arenzana, N., Hai, T., Minden, A., Prywes, R., (1998). Epidermal growth factor induction of the c-jun promoter by a Rac pathway. Mol. Cell. Biol. 18(2):1065-1073. Abstract