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case western reserve university

BIOCHEMISTRY
 
 

Dr. Edward Stavnezer

Professor

Pub Med:

Dr. Edward Stavnezer

Dr. Stavnezer's group studies the ski oncogene family.

The lab discovered ski due to its ability to transform cultured cells, but subsequently found that it also induces non-muscle cells to undergo terminal differentiation into skeletal muscle. To understand how ski influences these disparate cellular processes, Dr. Stavnezer's lab employs molecular genetic, biochemical, and immunological techniques. They have shown that ski-encoded proteins reside in the cell nucleus, and regulate transcription through association with sequence-specific DNA binding proteins including, NF-I and Smad2 and Smad3. The lab is studying how transcriptional regulation by Ski leads to transformation and myogenesis.

By in vitro mutagenesis combined with bacterial and retroviral expression systems, the group has mapped regions of the ski gene and of the related gene, sno, that are responsible for their biological activities. This work has identified protein domains responsible for dimerization of Ski and Sno, for transcriptional repression and for association with DNA binding and basal transcription factors. Mutation of ski and sno has failed to completely uncouple their transforming and differentiation-inducing functions but it has demonstrated a tight correlation between these activities and their ability to repress transcription. Using two-hybrid screens the group has identified several important transcriptional regulators including the TGF-b-activated Smad transcription factors as Ski/Sno interacting proteins. They have found that interaction of Ski and Sno with Smad proteins results in transcriptional repression. This is a reversal of Smad mediated transcriptional activation induced by TGF-b and  is mirrored in Ski's ability to block TGF-b inhibition of cellular proliferation. These results suggest that Ski acts as an oncogene by overcoming the tumor suppressing action of the TGF-b signaling pathway. Current efforts are focused on testing this idea, on the mechanism of repression and on the identification of regulated target genes using expression microarrays. Studies on human Ski have revealed that it is a phosphoprotein whose degree of phosphorylation is regulated during the cell cycle in both normal and transformed cells. Sites of phosphorylation and protein kinases responsible have been identified. Ongoing studies are probing both the functional consequences of phosphorylation and their role in Ski-induced transformation and differentiation.

Selected References

  • Xu, W. Angelis, K., Danielpour, D., Haddad, M. Bischof, O., Campisi, J., Stavnezer, E., Medrano, E., 2000 Ski acts as a co-repressor with Smad2 and Smad3 to regulate the response to TGF-b. Proc. Natl. Acad. Sci. USA 97: 5924-5929

  • Nicol, R., G. Zheng, P. Sutrave, D. Foster, and E. Stavnezer. Association of specific DNA binding and transcriptional repression with the transforming and myogenic activities of c-Ski. Cell Growth & Differentiation, 10:243-254 (1999)

  • S.B. Cohen, G. Zheng, H.C. Heyman and E. Stavnezer, Heterodimers of the SnoN and Ski oncoproteins form preferentially over homodimers and are more potent transforming agents. Nucleic Acids Res 27:1006-1014 (1999)

  • R. Nicol and E. Stavnezer, Transcriptional repression by v-Ski and c-Ski mediated by a specific DNA binding site. J. Biol. Chem. 273, 3588-3597 (1998)

  • S.B. Cohen, R. Nicol and Ed Stavnezer, A domain necessary for the transforming activity of SnoN is required for specific DNA binding, transcriptional repression and interaction with TAF(II)110. Oncogene. 1998 17, 2505-2513 (1998)

  • G. Zheng, J.T. Teumer, C. Colmenares, C. Richmond, and E. Stavnezer, Identification of a core functional and structural domain of the v-Ski oncoprotein responsible for both transformation and myogenesis. Oncogene 15 , 459-471 (1997)

  • P. Tarapore, C. Richmond, G. Zheng, S. B. Cohen, B. Kelder, J. Kopchick, U. Kruse, A. Sippel, C. Colmenares and E. Stavnezer, DNA binding and transcriptional activation by the Ski oncoprotein mediated by interaction with NFI. Nucleic Acids Res. 25, 3895-3903 (1997)

  • G. Zheng, K. Blumenthal, D.L. Shardy, and E. Stavnezer, High affinity dimerization by Ski involves parallel pairing of a novel bipartite a-helical domain. J. Biol. Chem. 272, 31855-31864 (1997)