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Clarence S Chan
Associate Professor Emeritus
Molecular Biosciences-
Research Summary:
Our research is focused on two basic processes that are critical for the proliferation and well being of all eukaryotic cells - chromosome segregation (i.e., mitosis) and the spatial control of cell growth and function (i.e., cell polarity). Defects in either process are known to result in many forms of human cancer.
Using the budding yeast S. cerevisiae as a model system and a combination of molecular genetic, cell biological and biochemical methods, we study the roles of the conserved Aurora/Ipl1 protein kinase complex and the Cdc42 GTPase in the control of these two processes. The Aurora/Ipl1 protein kinase regulates diverse processes during mitosis, including kinetochore-microtubule attachment, cell cycle checkpoint control, mitotic spindle stabilization and cytokinesis. The function of Aurora/Ipl1 is counteracted by that of protein phosphatase 1 (PP1).
We are studying the functional relationship between PP1 and Aurora/Ipl1; the proteins that are phosphorylated and thus regulated by Aurora/Ipl1; and additional proteins that regulate Aurora/Ipl1 function. The genes encoding subunis of the human Aurora/Ipl1 kinase complex are commonly de-regulated in a variety of human cancer, and pharmacological agents that inhibit Aurora function suppress tumorigenesis in mouse model systems.
Thus, our study of the yeast Aurora/Ipl1 complex likely will contribute to ongoing efforts to control human cancer. The Cdc42 GTPase plays a central role in regulating cell polarity in diverse organisms. When GTP-bound, Cdc42 binds to specific effector proteins that include Gic1 and Gic2 in yeast. These effector proteins in turn regulate the organization of the actin cytoskeleton and other cellular processes. We are studying how effectors such as Gic1 and Gic2 help to organize the actin cytoskeleton and what other protein may functionally interact with Gic1 and Gic2 in yeast.
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2010 Mok, J., P.M. Kim, H.Y.K. Lam, S. Piccirillo, X. Zhou, G.R. Jeschke, D.L. Sheridan, S.A. Parker, V. Desai, M. Jwa, E. Cameroni, H. Niu, M. Good, A. Remenyi, J.-L. N. Ma, Y.-J. Sheu, H.E. Sassi, R. Sopko, C.S.M. Chan, C. De Virgilio, N.M. Hollingsworth, W.A. Lim, D.F. Stern, B. Stillman, B.J. Andrews, M.B. Gerstein, M. Snyder, B.E. Turk, Deciphering protein kinase specificity through large-scale analysis of yeast phosphorylation site motifs, Science Signaling 3: ra12
2008 Jwa, M., J.-h. Kim, and C.S.M. Chan, Regulation of Sli15/INCENP, kinetochore and Cdc14 phosphatase functions by the ribosome biogenesis protein Utp7, J. Cell Biol. 182: 1099-1111
2008 Emanuele, M.J., W. Lan, M. Jwa, S.A. Miller, C.S.M. Chan, and P.T. Stukenberg, Aurora B kinase and protein phosphatase 1 have opposing roles in modulating kinetochore assembly., J. Cell Biol. 181: 241-254
2007 Wong, J., Y. Nakajima, S. Westermann, C. Shang, J.-s. Kang, C. Goodner, P. Houshmand, S. Fields, C.S.M. Chan, D. Drubin, G. Barnes, and T. Hazbun , A protein interaction map of the mitotic spindle., Mol. Biol. Cell 18: 3800-3809
2006 Gandhi, M., B.L. Goode, and C.S.M. Chan , Four novel suppressors of gic1 gic2 and their roles in cytokinesis and polarized cell growth in Saccharomyces cerevisiae., Genetics 174: 665-678
2005 Zhang, K., W. Lin, J.A. Latham, G.M. Riefler, J.M. Schumacher, C. Chan, K. Tatchell, D.H. Hawke, R. Kobayashi, and S.Y.R. Dent , The Set1 methyltransferase opposes Ipl1 Aurora kinase functions in chromosome segregation. , Cell 122: 723-734
2004 Chang, V.K., J.J. Donato, C.S. Chan, and B.K. Tye , Mcm1 promotes replication initiation by binding to specific elements at replication origins. , Mol. Cell. Biol. 24: 6514-6524
2003 Henry, K.R., K. DHondt, J.S. Chang, D.A. Nix, M.J.T.V. Cope, C.S.M. Chan, D.G. Drubin, and S.K. Lemmon, The actin-regulating kinase Prk1p negatively regulates Scd5p, a suppressor of clathrin deficiency, in actin organization and endocytosis. , Curr. Biol. 13: 1564-1569
2002 Mehta, S., X.M. Yang, C.S. Chan, M.J. Dobson, M. Jayaram, and S. Velmurugan , The 2 micron plasmid purloins the yeast cohesin complex: a mechanism for coupling plasmid partitioning and chromosome segregation? , J. Cell Biol. 158: 625-637
2002 Cheeseman, I.M., S. Anderson, M. Jwa, E. Green, J.-s. Kang, J.R. Yates III, C.S.M. Chan, D.G. Drubin, and G. Barnes, Phospho-regulation of kinetochore-microtubule attachments by the Aurora kinase Ipl1p. , Cell 111: 163-172
2001 Drees, B.L., B. Sundin, E. Brazeau, J.P. Caviston, G.-C. Chen, W. Guo, K.G. Kozminski, M.W. Lau, J.J. Moskow, A. Tong, L.R. Schenkman, A. McKenzie III, P. Brennwald, M. Longtine, E. Bi, C. Chan, P. Novick, C. Boone, J.R. Pringle, T.N. Davis, S. Fields, and D.G. Drubin , A protein interaction map for cell polarity development. , J. Cell Biol. 154: 549-571
2001 Kang, J.-s., I.M. Cheeseman, G. Kallstrom, S. Velmurugan, G. Barnes, and C.S.M. Chan, Functional cooperation of Dam1, Ipl1, and the inner centromere protein (INCENP)-related protein Sli15 during chromosome segregation. , J. Cell Biol. 155: 763-774
2000 Bi, E. J.B. Chiavetta, H. Chen, G.-C. Chen, C.S.M. Chan, and J.R. Pringle, Identification of novel, evolutionarily conserved Cdc42p-interacting proteins and of redundant pathways linking Cdc24p and Cdc42p to actin polarization in yeast, Mol. Biol. Cell. 11: 773-793
2000 Velmurugan, S., X.-M. Yang, C.S.-M. Chan, M. Dobson, and M. Jayaram, Partitioning of the 2-m circle plasmid of Saccharomyces cervisiae: functional coordination with chromosome segregation and plasmid-encoded Rep protein distribution, J Cell Biol. 149: 553-566
1999 Kim, J.-H., J.-S. Kang, and C.S.M. Chan , Sli15 associates with the Ipl1 protein kinase to promote proper chromosome segregation in Saccharomyces cerevisiae., J. Cell Biol. 145: 1381-1394
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