Michael D Mendenhall

Research Description: 

 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.

PubMed Publications: 

  • Latta, C.H.;Sudduth, T.L.;Weekman, E.M.;Brothers, H.M.;Abner, E.L.;Popa, G.J.;Mendenhall, M.D.;Gonzalez-Oregon, F.;Braun, K.;Wilcock, D.M. "Determining the role of IL-4 induced neuroinflammation in microglial activity and amyloid-β using BV2 microglial cells and APP/PS1 transgenic mice." Journal of neuroinflammation 12, 1 (2015): 243. [PubMed Link] | [ Full text ]
  • Weekman, E.M.;Sudduth, T.L.;Abner, E.L.;Popa, G.J.;Mendenhall, M.D.;Brothers, H.M.;Braun, K.;Greenstein, A.;Wilcock, D.M. "Transition from an M1 to a mixed neuroinflammatory phenotype increases amyloid deposition in APP/PS1 transgenic mice." Journal of neuroinflammation 11, (2014): 127. [PubMed Link] | [ Full text ]
  • Cummins, T.D.;Mendenhall, M.D.;Lowry, M.N.;A Korte, E.;Barati, M.T.;Khundmiri, S.J.;Salyer, S.A.;Klein, J.B.;Powell, D.W. "Elongin C is a mediator of Notch4 activity in human renal tubule cells." Biochimica et biophysica acta 1814, 12 (2011): 1748-57. [PubMed Link] | [ Full text ]
  • Hassane, D.C.;Lee, R.B.;Mendenhall, M.D.;Pickett, C.L. "Cytolethal distending toxin demonstrates genotoxic activity in a yeast model." Infection and immunity 69, 9 (2001): 5752-9. [PubMed Link] | [ Full text ]
  • Nash, P.;Tang, X.;Orlicky, S.;Chen, Q.;Gertler, F.B.;Mendenhall, M.D.;Sicheri, F.;Pawson, T.;Tyers, M. "Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication." Nature 414, 6863 (2001): 514-21. [PubMed Link] | [ Full text ]
  • Schneider, B.L.;Patton, E.E.;Lanker, S.;Mendenhall, M.D.;Wittenberg, C.;Futcher, B.;Tyers, M. "Yeast G1 cyclins are unstable in G1 phase." Nature 395, 6697 (1998): 86-9. [PubMed Link] | [ Full text ]
  • Mendenhall, M.D.;Hodge, A.E. "Regulation of Cdc28 cyclin-dependent protein kinase activity during the cell cycle of the yeast Saccharomyces cerevisiae." Microbiology and molecular biology reviews : MMBR 62, 4 (1998): 1191-243. [PubMed Link] | [ Full text ]
  • Mendenhall, M.D. "Cyclin-dependent kinase inhibitors of Saccharomyces cerevisiae and Schizosaccharomyces pombe." Current topics in microbiology and immunology 227, (1998): 1-24. [PubMed Link] |
  • Mendenhall, M.D.;, W.;Nugroho, T.T. "The Cdc28 inhibitor p40SIC1." Progress in cell cycle research 1, (1995): 173-85. [PubMed Link] |
  • Schwob, E.;Böhm, T.;Mendenhall, M.D.;Nasmyth, K. "The B-type cyclin kinase inhibitor p40SIC1 controls the G1 to S transition in S. cerevisiae." Cell 79, 2 (1994): 233-44. [PubMed Link] | [ Full text ]
  • Nugroho, T.T.;Mendenhall, M.D. "An inhibitor of yeast cyclin-dependent protein kinase plays an important role in ensuring the genomic integrity of daughter cells." Molecular and cellular biology 14, 5 (1994): 3320-8. [PubMed Link] | [ Full text ]
  • Mendenhall, M.D. "An inhibitor of p34CDC28 protein kinase activity from Saccharomyces cerevisiae." Science (New York, N.Y.) 259, 5092 (1993): 216-9. [PubMed Link] | [ Full text ]
  • Hadwiger, J.A.;Wittenberg, C.;Mendenhall, M.D.;Reed, S.I. "The Saccharomyces cerevisiae CKS1 gene, a homolog of the Schizosaccharomyces pombe suc1+ gene, encodes a subunit of the Cdc28 protein kinase complex." Molecular and cellular biology 9, 5 (1989): 2034-41. [PubMed Link] | [ Full text ]
  • Mendenhall, M.D.;Culbertson, M.R. "The yeast SUF3 frameshift suppressor encodes a mutant glycine tRNA(CCC)." Nucleic acids research 16, 17 (1988): 8713. [PubMed Link] | [ Full text ]
  • Ball, C.B.;Mendenhall, M.D.;Sandbaken, M.G.;Culbertson, M.R. "The yeast SUF5 frameshift suppressor encodes a mutant glycine tRNA(CCC)." Nucleic acids research 16, 17 (1988): 8712. [PubMed Link] | [ Full text ]
  • Mendenhall, M.D.;Richardson, H.E.;Reed, S.I. "Dominant negative protein kinase mutations that confer a G1 arrest phenotype." Proceedings of the National Academy of Sciences of the United States of America 85, 12 (1988): 4426-30. [PubMed Link] | [ Full text ]
  • Mendenhall, M.D.;Jones, C.A.;Reed, S.I. "Dual regulation of the yeast CDC28-p40 protein kinase complex: cell cycle, pheromone, and nutrient limitation effects." Cell 50, 6 (1987): 927-35. [PubMed Link] | [ Full text ]
  • Mendenhall, M.D.;Leeds, P.;Fen, H.;Mathison, L.;Zwick, M.;Sleiziz, C.;Culbertson, M.R. "Frameshift suppressor mutations affecting the major glycine transfer RNAs of Saccharomyces cerevisiae." Journal of molecular biology 194, 1 (1987): 41-58. [PubMed Link] | [ Full text ]
  • Winey, M.;Mendenhall, M.D.;Cummins, C.M.;Culbertson, M.R.;Knapp, G. "Splicing of a yeast proline tRNA containing a novel suppressor mutation in the anticodon stem." Journal of molecular biology 192, 1 (1986): 49-63. [PubMed Link] | [ Full text ]
  • Reed, S.I.;Barros Lopes, M.A.;Ferguson, J.;Hadwiger, J.A.;Ho, J.Y.;Horwitz, R.;Jones, C.A.;Lörincz, A.T.;Mendenhall, M.D.;Peterson, T.A. "Genetic and molecular analysis of division control in yeast." Cold Spring Harbor symposia on quantitative biology 50, (1985): 627-34. [PubMed Link] |