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Faculty
Curt Wittenberg
Professor
Department of Molecular Biology
TSRI - 1986
Joint Appointments CELL BIOLOGY
Education
Ph.D., University of California, - Santa Barbara, 1983
Research Focus
Control of Cell Cycle Initiation
Proper regulation of cell proliferation is of critical importance for the well-being of cells and organisms. Sequential waves of positive and negative regulators of cell cycle transitions maintain the organization of events. Transcriptional regulation coupled with phosporylation-dependent ubiquitin-mediated proteolysis is largely responsible for that regulation. Those processes are intimately coupled to the cell cycle regulatory machinery generating a highly coordinated autoregulatory system.
Cyclin dependent protein kinases (CDKs) and their regulators comprise the central elements of the eukaryotic cell cycle machinery. Cyclins, the positive regulatory subunits, are classic examples of periodically accumulating regulators. The G1 cyclin Cln3 promotes cell cycle initiation by stimulating the expression of a large family of G1-specific genes. Using genetics coupled with mass spectrometry-based protein identification, we have identified a number of novel proteins interacting with the G1-specific transcriptional machinery. One such protein, Whi5, acts as a negative regulator of G1-specific transcription that, like the human tumor suppressor Rb, restricts cell cycle initiation. Phosphorylation of Whi5 by Cln3/CDK promotes dissociation from the transcription factors activating transcription and driving cell proliferation. Continued dissection of that pathway will provide insight into mechanisms of human disease.
G1 cyclins are degraded via phosphorylation-dependent ubiquitination. Recognition of phosphorylated substrates by the E3 ubiquitin ligase SCF is highly conserved in eukaryotes. In addition to revealing the basis for recognition of phosphorylated Cln2, analysis of the F box protein Grr1, the specificity component of SCF, has led to identification of novel targets required for nutrient-regulated transcription. We find that distinct properties of Grr1are required for recognition of Cln2 and other targets. Further understanding of that specificity and the regulation of SCFGrr1 targets offers a window into the mechanisms by which transcription regulation is linked to proteolysis.
Selected References
de Bruin, R., McDonald, W.H., Kalashnikova, T.I., Yates, J., 3rd, and C. Wittenberg (2004) Cln3 Activates G1-specific Transcription by Promoting Dissociation of the SBF-Bound Repressor, Whi5. Cell 117, 887-898.
Spielewoy, N., Flick, K., Kalashnikova, T.I., Walker, J.R., and C. Wittenberg. (2004) Regulation and recognition of SCFGrr1 targets in the glucose and amino acid signaling pathways. Mol. Cell. Biol. 24, In press
Kesti, T., McDonald, W.H., Yates, J.R, 3rd, and C. Wittenberg (2004) Cell cycle dependent phosphorylation of the DNA polymerase epsilon subunit, Dpb2, by the Cdc28 cyclin-dependent protein kinase. J. Biol. Chem. 279:14245-14255.
Flick, K., Spielewoy, N., Kalashnikova, T., Guadderama, M., Zhu, Q., and C. Wittenberg (2003) Grr1 dependent degradation of Mth1 mediates glucose induction of HXT gene expression by promoting dissociation of Rgt1 from HXT gene promoters. Molecular Biology of the Cell, 4: 3230-3241
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