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2009 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report 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. Staff Students Visiting Scientists Brendan Looyenga, Ph.D. Amy Nelson 30 Megan Goodall, B.S. Jon Karnes, B.S. Michael Shaheen, B.S. Katie Sian, B.S. Laura Westrate, B.S. Natalie Wolters, B.S. Cheri Ackerman James Hogan Bodour Salhia, Ph.D. Brad Brooks, Ph.D.

VARI | 2009 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, proliferation, and 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 several essential kinases and phosphatases whose roles in cell survival were previously unrecognized. We are asking several questions. How are these 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? Mitochondrial dysfunction in cancer Mitochondria are dynamic organelles that house many crucial cellular processes. While mitochondria are best known for producing more than 90% of cellular ATP and for releasing cytochrome c during apoptosis, they also modulate mitochondrial dynamics and ion homeostasis, oxidize carbohydrates and fatty acids, and participate in numerous other molecular signaling pathways. Disruption of mitochondrial function contributes to the etiology of at least fifty diseases, including cancer, underscoring the importance of identifying the molecular components that regulate normal and pathological function in these organelles. Similar to the discovery of the BCL-2 Figure 1 family members, which play key roles in mitochondrial apoptosis, the discovery of enzymes that regulate mitochondrial function (cytochrome c release, ATP production, and fission/fusion) will provide critical insights into the physiology of this organelle and how this physiology is disrupted in cancer. Figure 1. Mitochondrial dynamics as visualized by MitoTraker staining (red). As an outcome, mitochondrial dysfunction from a single kinase or phosphatase may have consequences that range from defects in energy metabolism to the etiology of complex diseases such as cancer. Our preliminary data with a mitochondrial kinase and two different mitochondrial phosphatases demonstrate that, when lost, the kinase decreases ATP production and drives mitochondrial fusion, while each phosphatase studied leads to an increase in ATP production. We have data that excessive or even modest increases in ATP levels may completely prevent mitochondrialdependent apoptosis. The significance of our work is that we have identified the specific mitochondrial signaling proteins that interact in a complex with key components of the electron transport chain and also with the mitochondrial fission/fusion machinery. Related to this, we have also identified a mitochondrial-specific kinase that controls the dynamic nature of the mitochondria, specifically mitochondrial fission and fusion. 31

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