11 months ago

2008 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report Monitoring cellular signaling Phosphatidylinositol-3-kinase (PI3K) phosphorylates the 3´ ring position of phosphatidylinositol to generate lipid products important for signal transduction, membrane trafficking, and other cellular processes. The identification of PI3Ks as key players in cellular functions ranging from vesicular trafficking to cell survival merits further study to identify factors acting immediately upand downstream of these lipid kinases, as well as characterizing the phosphatase regulating these molecular pathways. Roles for PI3K isoforms in amino acid sensing and in signaling through the mTOR pathway, as well as in autophagy, have also recently emerged. Note that these functions of PI3Ks might not merely rely on their lipid kinase activity, since they are large enzymes that could also serve as platforms for the assembly of protein complexes. Understanding is needed of the mechanisms of PI3K signaling involved in these various cellular functions. Parkinson disease–associated genes in cancer Renal cell carcinoma (RCC) is an aggressive cancer that is highly metastatic and refractory to all forms of systemic cancer therapy. Using bioinformatic analysis and over 150 RCC tumor samples, we have identified Parkinson disease–associated (PD) kinases as a novel molecular constituent of the renal tubule epithelium whose expression is specifically down-regulated during the progression of papillary RCC (Figure 2). These PD kinases are highly expressed in the brain and kidney and have been previously linked to familial Parkinson disease. Activating mutations in these genes sensitize cells to oxidative stress and lead to increased death of neural cells, implying that these genes may function as a sensor of oxidative stress in the renal epithelium and induce cell death pathways in response to toxic levels of reactive oxygen species. Selective loss of each gene in more aggressive and metastatic RCC tumors suggests that this protein may also be a tumor suppressor. The goal of this project is to define the relationship between oxidative stress management and malignant tumor progression in the kidney, with a particular emphasis on the role of kinase signaling. This project is a collaboration with VARI’s Kyle Furge and Bin Teh. Figure 2 Figure 2. PD genes are located within a conserved RCC amplicon on chromosome 12. Expression profiles from more than 150 normal and RCC tissue samples were obtained by microarray analysis with the Affymetrix HGU-133 Plus 2.0 chip. 36

VARI | 2008 Colorectal cancer Chemoresistance is a therapeutic problem that severely limits successful treatment of most human cancers. This is particularly true of colorectal cancer, in which the development of resistance is common: most anti-cancer regimens are ineffective, with the five-year survival rates for late-stage colorectal cancer being only 8%. How colorectal cancer resistance develops is largely unknown, and the response to therapy varies based on individual patient tumors. With this in mind, how can we prevent cancer emergence or progression at the level of individual tumors? Recent studies have shown that a large percentage of colorectal tumors have mutations in a key gene, for class I PI3K. While mutations play an important causative role in colorectal cancer, it is currently unclear how these mutations can be exploited as drug targets and whether we can develop targeted cancer agents based on the gene. We have ongoing projects to determine the molecular pathways (and genes) that can be used to prevent progression of precancerous lesions to colorectal cancer. Further, we are defining each pathway activation in each patient’s tumor and comparing the pathways with a novel chemopreventive agent against PI3K/mTOR. Graded MAPK signaling and switch-like c-Fos induction We also take a systems biology approach to understanding two key molecular pathways, Ras/MAPK and PI3K/mTOR. One project in the lab involves the question of whether the evolutionarily conserved pathways exhibit a switch-like or a graded response in mammalian cells. Ultrasensitive switch-like responses control cell-fate decisions in many biological settings, and the regulation of kinase activity is one way in which such behavior can be initiated. Signaling molecules switch between two discontinuous, stable states with no intermediate; this is referred to as a bistable response. Given the irreversible, all-or-none nature of many cell behaviors, including cell cycle control and apoptosis, significant effort has been focused on identifying the cellular mechanisms underlying bistability. Recent Publications From left: Wolters, Nelson, MacKeigan, Looyenga, DeHaan, Church, Crissman, Sian, McElliott Elis, W., E. Triantafellow, N.M. Wolters, K.R. Sian, G. Caponigro, J. Borawski, L.A. Gaither, L.O. Murphy, P. Finan, and J.P. MacKeigan. 2008. Downregulation of class II PI3Ka expression below a critical threshold induces apoptotic cell death. Molecular Cancer Research 6(4): 614–623. Wolters, N.M., and J.P. MacKeigan. 2008. From sequence to function: using RNAi to elucidate mechanisms of human disease. Cell Death and Differentiation 15(5): 809–819. 37

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