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Ron Prywes
Co-Director of Graduate Studies
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 proteins is involved in at least one step in the complex pathways of cellular growth control.

We have been trying to further understand these cellular signaling pathways that control cell growth by studying one of the earliest steps. Quiescent cells can be induced to divide by treatment with growth factors. One of the first consequences is induction of gene expression of a class of genes called cellular immediate early genes (IEGs). A paradigm of these immediate early genes is the proto-oncogene c-fos. Transcriptional activation of c-fos is mediated by a sequence element in its promoter, the Serum Response Element (SRE). A specific transcription factor, Serum Response Factor (SRF), binds the SRE and is required for expression of many IEGs.

SRF is activated by two signaling pathways. One is MAP kinase phosphorylation of the SRF cofactors, the ternary complex factors (TCFs), and the second is signaling through the small GTPase RhoA. The RhoA pathway works through the myocardin-related family of SRF coactivators (MKL1 and MKL2). The RhoA pathway causes changes in the actin cytoskeleton of the cell and changes in actin filaments directly control activation of MKL1 and MKL2. We are currently studying how MKL1/2 are regulated and what additional factors regulate expression of SRF target genes.

MKL1 was originally identified at a translocation breakpoint in megakaryoblastic leukemia. Activation of MKL1 and of SRF target genes is likely responsible for this leukemia. The role of this pathway in cancer is further shown by studies of the Rho family which show a role in cancer metastasis and of an inhibitor of RhoA, Deleted in Liver Cancer 1 (DLC1), which is thought to be a tumor suppressor for many types of cancer. We are interested in whether MKL1 and SRF act as downstream actors for stimulation of cancer by the DLC1/RhoA pathway and how this pathway might be inhibited.

While expression of many cellular immediate early genes is regulated by SRF, many IEGs are regulated by other factors and pathways. We have initiated a project to understand regulation of these SRF-independent IEGs to identify new pathways involved in control of cell growth.

MedLine Listing of Dr. Prywes's Publications
Representative Recent Publications
  • Lee, S.M., Vasishtha, M. and Prywes, R. (2010) Activation and repression of cellular immediate early genes by SRF cofactors. J Biol Chem. Epub ahead of print: 2010 May 12. Article
  • Muehlich, S., Wang, R., Lee, S.M., Lewis, T.C., Dai C. and Prywes, R. (2008) Serum-induced phosphorylation of the SRF coactivator MKL1 by the ERK1/2 pathway inhibits its nuclear localization Mol. Cell. Biol. 28(20): 6302-13. Article
  • Shen, J., Snapp, E.L., Lippincott-Schwartz, J. and Prywes, R (2005) Stable binding of ATF6 to BiP in the ER stress response Mol. Cell. Biol 25(3): 921-32. Article
  • Shen, J. and Prywes, R. (2005) ER stress signaling by regulated proteolysis of ATF6. Methods 35(4): 382-9. Article
  • Selvaraj, A. and Prywes, R. (2004) Expression profiling of serum inducible genes identifies a subset of SRF target genes that are MKL dependent. BMC Mol. Biol 5(1): 13. Article
  • Shen, J. and Prywes, R. (2004) Dependence of site-2 protease cleavage of ATF6 on prior site-1 protease digestion is determined by the size of ATF6's lumenal domain J. Biol. Chem 279(41): 43046-51. Article
  • Cen, B., Selvaraj, and Prywes, R. (2004) The Myocardin/MKL family of SRF coactivators: key regulators of immediate early and muscle specific gene expression J. Cell. Biochem 93(1): 74-82. Article
  • Selvaraj, A. and Prywes, R. (2003) Megakaryoblastic Leukemia-1/2, a transcriptional co-activator of SRF, is required for skeletal myogenic differentiation J. Biol. Chem. 278(43): 41977-87. Article
  • Cen, B., Selvaraj, A., Burgess, R.C., Hitzler, J.K., Ma, Z., Morris, S.W. and Prywes, R. (2003) Megakaryoblastic Leukemia-1, a potent transcriptional coactivator for Serum Response Factor, is required for serum induction of SRF target genes Mol. Cell. Biol. 23: 6597-6608. Article
Ron Prywes