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2007 Scientific Report

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VARI |

VARI | 2007 Jeffrey P. MacKeigan, Ph.D. Laboratory of Systems Biology Dr. MacKeigan received his Ph.D. in microbiology and immunology at the University of North Carolina Lineberger Comprehensive Cancer Center in 2002. He then served as a postdoctoral fellow in the laboratory of John Blenis in the Department of Cell Biology at Harvard Medical School. In 2004, he joined Novartis Institutes for Biomedical Research in Cambridge, Massachusetts, as an investigator and project leader in the Molecular and Developmental Pathways expertise platform. Dr. MacKeigan joined VARI in June 2006 as a Scientific Investigator. 35 Staff Students Laboratory Staff Students Visiting Scientists Brendan Looyenga, Ph.D. Christina Ludema, B.S. Natalie Wolters, B.S. Katie Sian, B.S. Geoff Kraker

Van Andel Research Institute | Scientific Report Research Interests The primary focus of the Systems Biology laboratory is identifying and understanding the genes and signaling pathways that when mutated contribute to the pathophysiology of cancer. We take advantage of RNA interference (RNAi) and novel proteomic approaches to identify the enzymes that control cell growth, cell proliferation, and cell survival. For example, after screening the human genome for more than 600 kinases and 200 phosphatases—called the “kinome” and “phosphatome”, respectively—that act with chemotherapeutic agents in controlling apoptosis, we identified 73 kinases and 72 phosphatases whose roles in cell survival were previously unrecognized. We are asking several questions. How are these novel survival enzymes regulated at the molecular level? What signaling pathway(s) do they regulate? Does changing the number of enzyme molecules present inhibit waves of compensatory changes at the cellular level (system-level changes)? What are the system-level changes after reduction or loss of each gene? Identification of kinases that regulate cell survival 36 We have performed RNAi screens in the presence of apoptosis-inducing chemotherapeutic agents (Taxol, cisplatin, and etoposide) and identified a group of kinases whose loss of function sensitizes cells to undergo cell death, the most interesting of these being PINK1 (PTEN-induced kinase 1). PINK1 was originally shown to be up-regulated by the tumor suppressor PTEN. Although PINK1 does not fall into a particular kinase subfamily, it has a known role in maintaining mitochondrial membrane potential. Other work has recently shown inherited mutations at chromosomal location 1p36 in familial Parkinson disease, and the two mutated genes that map to this region are PINK1 (PARK6) and DJ-1 (PARK7). Both genes are responsible for early-onset autosomal recessive parkinsonism. We had previously noted that DJ-1 is overexpressed in non–small cell lung carcinoma and that its down-regulation enhances apoptosis. Further, Parkinson disease–causing mutations in LRRK2 (PARK8), which are dominantly inherited gain-of-function mutations, sensitize neurons to cell death, and a significant fraction of the LRRK2 population is associated with the mitochondria. We are currently investigating whether the molecular mechanisms of PINK1 and LRRK2 in cancer and in Parkinson disease are linked.

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