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Michael D. Mendenhall Research Interests | Publications | PubMed
 Cell division is a highly complex process requiring the coordinated synthesis and assembly of all the components needed to form a copy of the original cell. Genetic defects that result in the misregulation of any of these events, when not lethal, often lead to the production of damaged daughter cells. In metazoans, individuals carrying these defects have increased risks of having birth defects or cancer. Much of the coordination of cell cycle events is achieved through the control of the cyclin-dependent protein kinases (CDKs), of which p34cdc2 is the best known. Two principal means of controlling this kinase have been described: (1) activating and inhibiting phosphorylations and dephosphorylations of the protein kinase itself and (2) regulated synthesis and degradation of the cyclin components. We have identified a third mechanism: inhibition by complex formation with a 32 kD protein, encoded by the yeast SIC1 gene, that blocks access to the CDK substrates. Genetic disruption of SIC1 results in viable cells that generate chromosomal abnormalities that include breakage and loss at a high rate. These events occur in a "stem cell" type pattern in which the chromosomal abnormalities appear to occur in only one of the daughter cells at each division leaving one cell that is always normal. Overproduction of the SIC1 protein in vivo arrests cell division with a pattern that suggests that a specific subset of the cyclin-CDK complexes are being inhibited, a pattern that agrees with our biochemical analysis. We postulate that SIC1 part of a system of inhibitory constraints that when lost leads to premature cell division that in turn produces the chromosomal aberrations. Recent studies in animal cells indicate that tumor suppressors such as retinoblastoma and p53 may be involved in similar types of constraints on cell division. These proteins are also known to form physcial associations with various cyclins in normal cells. We are continuing a multifaceted analysis of this gene and its gene product in yeast cells to learn how and when it interacts with the kinase and how it is in turn regulated. In addition we have obtained evidence that SIC1 is highly conserved and are extending our studies to vertebrate systems.
Mendenhall, M.D. An Inhibitor of p34CDC28 Protein Kinase Activity From Saccharomyces cerevisiae. Science 259:216-219, 1993. Nugroho, T.T. and M.D. Mendenhall An inhibitor of yeast cyclin-dependent protein kinase plays an important role ensuring the genomic integrity of daughter cells, Mol. Cell Biol. 14:3320-3328, 1994. Schwob, E., T. Böhm, M.D. Mendenhall and K. Nasmyth The B-type cyclin kinase inhibitor p40SIC1 controls the G1/S transition in Saccharomyces cerevisiae. Cell 79:233-244, 1994.
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