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2007 Scientific Report

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VARI | 2007 We are also studying the human Cdc7-Dbf4 protein kinase, called here HsCdc7-Dbf4. The HsCdc7 protein is up-regulated in about 50% of the NCI 60 tumor cell lines representing the most common forms of cancer in the USA. In contrast, HsCdc7 protein has very low abundance or is undetectable in normal cells and tissues. It may be that nondividing cells down-regulate HsCdc7 expression. We have further determined by immunohistochemistry that HsCdc7 protein is highly expressed in some primary human tumors. Since HsCdc7 is an essential kinase required for DNA replication, its increased expression level in some tumors and tumor cell lines may reflect higher rates of cellular proliferation. Alternatively, since HsCdc7 is involved in other aspects of chromosome metabolism (e.g., DNA repair) and functions in the S-phase checkpoint, its increased expression may offer an advantage to tumor cells that have higher rates of chromosome instability. It was therefore interesting when we discovered several years ago that knockdown of HsCdc7 expression using RNAi results in an apoptotic response in some cancer cell lines but not in normal cells. We have been examining the molecular differences for this apoptotic response. Apoptosis occurs in cells lines that are either p53 wild type or phenotypically null for p53. There is good published evidence that in response to HsCdc7 depletion, wild-type cells undergo a G1 and G2/M arrest that is p53-dependent and protects against apoptosis. However, in some cancer cell lines, even in the absence of p53 function, HsCdc7 knockdown does not induce apoptosis, although these cells are otherwise competent to undergo the apoptotic program in response to various stimuli. Since HsCdc7 is required for DNA replication and apparently plays a role in other aspects of chromosome metabolism, we think that these findings have significance for inhibiting the growth and/or viability of certain types of tumor cells. 77 Recent Publications From left: Chen, Miller, Savreux, Weinreich, Crampton, Gabrielse, Chang, Haste Gabrielse, Carrie, Charles T. Miller, Kristopher H. McConnell, Aaron DeWard, Catherine A. Fox, and Michael Weinreich. 2006. A Dbf4p BRCA1 C-terminal-like domain required for the response to replication fork arrest in budding yeast. Genetics 173(2): 541–555. Zhang, Chun, Dong Kong, Min-Han Tan, Donald L. Pappas, Jr., Peng-Fei Wang, Jindong Chen, Leslie Farber, Nian Zhang, Han-Mo Koo, Michael Weinreich, Bart O. Williams, and Bin Tean Teh. 2006. Parafibromin inhibits cancer cell growth and causes G1 phase arrest. Biochemical and Biophysical Research Communications 350(1): 17–24.

Van Andel Research Institute | Scientific Report Bart O. Williams, Ph.D. Laboratory of Cell Signaling and Carcinogenesis 78 Dr. Williams received his Ph.D. in biology from Massachusetts Institute of Technology in 1996. For three years, he was a postdoctoral fellow at the National Institutes of Health in the laboratory of Harold Varmus, former Director of NIH. Dr. Williams joined VARI as a Scientific Investigator in July 1999 and was promoted to Senior Scientific Investigator in 2006. Staff Charlotta Lindvall, M.D., Ph.D. Dan Robinson, Ph.D. Cassandra Zylstra, B.S. Students Sarah Mange Amanda Field

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