Don Cleveland, PhD

Research Interests

Cleveland is interested in the genes and proteins involved in mitotic spindle assembly and faithful chromosome segregation just prior to division.  This process is particularly relevant to the development of cancer because it is thought that cancer cells mis-segregate chromosomes due to errors in mitosis resulting in aneuploidy. The major pathway guarding against whole chromosome mis-segregation is the mitotic checkpoint, a cell cycle control mechanism in which the centromeres of unattached chromosomes generate an inhibitor that blocks cyclin B degradation and advance across mitosis. The antitumor drug taxol is effective by chronically activating this checkpoint. In the past year, starting from all purified components Cleveland’s efforts have reconstructed mitotic checkpoint signaling in vitro. Additionally, abnormalities in number of microtubule organizing centers (centrosomes) can promote errors in spindle formation that lead to subsequent chromosome missegregation and extra centrosomes are associated with many cancers. Like DNA, centrosomes are duplicated only once each cell cycle. The duplication process is governed by polo-like kinase 4 (Plk4). Cleveland’s recent efforts identified how centrosome over-replication is blocked: kinase-mediated, autoregulated instability of Plk4 acts to self-limit Plk4 activity so as to prevent centrosome amplification.

Clinical

• Cancer Biology
• Amyotrophic lateral sclerosis

Publications (selected)

• Weaver, B.A.A., Silk, A.D., Montagna, C., Verdier-Pinard, P. and Cleveland, D.W. (2007). Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell 11, 25-36.
• Yamanaka, K., Chun, S.J., Boillee, S., Fujimori, N., Yamashita, H., Gutmann, D.H., Misawa, H., Takahashi, R., and Cleveland, D.W. (2008). Astrocytes as determinants of disease progression in inherited ALS. Nat. Neurosci. 11, 251-253.
• Kulukian, A., Han, J.-S. and Cleveland, D.W. (2009). Catalytic amplification by unattached kinetochores of a diffusible wait anaphase inhibitor requires a Mad2 template to prime BubR1 for Ccd20 binding. Dev. Cell. 16, 105-117.
• Foltz, D.R., Jansen, L.E.T., Bailey, A.O., Yates, J.R, Wood, S., Basset, E.A., Black, B.E., and Cleveland, D.W. (2009). Centromere specific assembly of CENP-A nucleosomes is mediated by HJURP. Cell 137, 472-484.
  Lagier-Tourenne, C. and Cleveland, D.W. (2009). Rethinking ALS: the FUS about TDP-43. Cell 136, 1001-1004.
• Kim, Y., Holland, A.J., Lan, W. and Cleveland, D.W. (2010). Aurora kinases mediate chromosome congression through regulation of CENP-E. Cell, in press.