Biochemistry Department - Primary Faculty
Edward Stavnezer, Ph.D.
The lab discovered the Ski oncogene 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, Smad3 and Six1. The lab is studying how transcriptional regulation by Ski leads to transformation and myogenesis.
By in vitro mutagenesis, bacterial and retroviral expression, the group has mapped regions of the ski gene and of the related gene, SnoN, 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 SnoN 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 regulate transcription. 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 reverses Smad mediated transcriptional activation induced by TGF-b and thereby blocks 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.
Using regulated overexpression and knock-down technology, the lab has found that Ski expression stimulates and is necessary for terminal skeletal muscle differentiation. Once again this activity is mediated by its interaction with a DNA-binding transcription factor, in this case, Six1. In a complex with Six1, Ski acts a co-activator to control the expression of the key muscle regulatory gene, myogenin. Ongoing collaborative work focuses on the role of Ski in early muscle development, neural development, cellular metabolism and human melanoma.
Chen D, Lin Q, Box N, Roop D, Ishii S, Matsuzaki K, Fan T, Hornyak TJ, Reed JA, Stavnezer E, Timchenko NA, Medrano EE.
“ SKI knockdown inhibits human melanoma tumor growth in vivo. ”
Pigment Cell Melanoma Res 22:761-72(2009)
Zhang H, Stavnezer E.
“ Ski regulates muscle terminal differentiation by transcriptional activation of Myog in a complex with Six1 and Eya3. ”
J Biol Chem. 284:2867-79 (2009)
Atanasoski S, Notterpek L, Lee HY, Castagner F, Young P, Ehrengruber MU, Meijer D, Sommer L, Stavnezer E, Colmenares C, Suter U.
“ The protooncogene Ski controls Schwann cell proliferation and myelination. ”
Neuron 43:499-511 (2004)
Chen D, Xu W, Bales E, Colmenares C, Conacci-Sorrell M, Ishii S, Stavnezer E, Campisi J, Fisher DE, Ben-Ze'ev A, Medrano EE.
“ SKI activates Wnt/beta-catenin signaling in human melanoma. ”
Cancer Res. 63:6626-34 (2003).
Xu, W. Angelis, K., Danielpour, D., Haddad, M. Bischof, O., Campisi, J., Stavnezer, E., Medrano, E.
“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 (2000)
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)
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- Lab: RT40