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2007 Scientific Report

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VARI | 2007 • Effect of hypoxia-inducible factor signaling on dopaminergic cell survival. Dopaminergic neurons are exquisitely sensitive to oxidative stress, which is defined by an increase in toxic reactive oxygen species. Reactive oxygen species lead to cell death by direct mechanisms, such as damage to important cellular biomolecules, and indirect ones, such as the induction of cell death pathways. The latter effect may be offset by cell survival pathways, which increase thethreshold signal intensity required to induce cell death. Because both chemically induced and idiopathic Parkinson disease are characterized by increased oxidative stress in dopaminergic neurons, therapies that increase cell survival pathways in these neurons may be broadly applicable as a treatment to decrease cell death in patients. The PI-3-kinase (PI3K)/Akt pathway is a highly conserved cell survival pathway operating in virtually all mammalian cell types. This pathway is tightly regulated by the phosphatase PTEN, which directly opposes the kinase activity of PI3K. We have crossed DAT-cre mice to mice with a conditionally inactivated allele for PTEN (PTEN flox/flox ). Expression of the cre recombinase in these mice leads to a genetic deletion of PTEN, thereby increasing Akt activity. DAT-cre/PTEN flox/flox mice and their wild-type littermates will be treated with the neurotoxin MPTP, which induces high levels of oxidative stress in dopaminergic neurons. We will compare the mice using behavioral and histological parameters to determine whether increased Akt activity leads to greater cell survival after an oxidative stress insult. Educational highlights This year we had one student from GRAPCEP, two students from the MSU-CVM program, and a guest student from Bath University in the United Kingdom. Our GRAPCEP mentorship program continues to be funded by Pfizer for a seventh year. Dr. Resau is a member of the graduate school committee that established the VAEI Graduate School, which will increase our research and educational opportunities. 49 From left, back row: Goolsby, Satterthwaite, Norton, Resau, Haak, Hudson; front row: Kort, Luo, VandenBeldt, Berghuis, Jason, Ramirez, Looyenga

Van Andel Research Institute | Scientific Report Recent Publications Baldus, S.E., E.J. Kort, P. Schirmacher, H.P. Dienes, and J.H. Resau. In press. Quantification of MET and hepatocyte growth factor/scatter factor expression in colorectal adenomas, carcinomas, and non-neoplastic epithelia by quantitative laser scanning microscopy. International Journal of Oncology. Kort, E.J., M.R. Moore, E.A. Hudson, B. Leeser, G.M. Yeruhalmi, R. Leibowitz-Amit, G. Tsarfaty, I. Tsarfaty, S. Moshkovitz, and J.H. Resau. In press. Use of organ explant and cell culture. In Mechanisms of Carcinogenesis, Hans Kaiser, ed. Dordrecht, The Netherlands: Kluwer Academic. Lindemann, K.K., J. Resau, J. Nährig, E. Kort, B. Leeser, K. Anneke, A. Welk, J. Schäfer, G.F. Vande Woude, E. Lengyel, and N. Harbeck. In press. Differential expression of c-Met, its ligand HGF/SF, and HER2/neu in DCIS and adjacent normal breast tissue. Histopathology. Whitwam, T., M.W. VanBrocklin, M.E. Russo, P.T. Haak, D. Bilgili, J.H. Resau, H.-M. Koo, and S.L. Holmen. In press. Differential oncogenic potential of activated RAS isoforms in melanocytes. Oncogene. Young, J.J., J.L. Bromberg-White, C.R. Zylstra, J. Church, E. Boguslawski, J. Resau, B.O. Williams, and N. Duesbery. In press. LRP5 and LRP6 are not required for protective antigen–mediated internalization or lethality of anthrax lethal toxin. PLoS Pathogen. 50 Bruxvoort, Katia J., Holli M. Charbonneau, Troy A. Giambernardi, James C. Goolsby, Chao-Nan Qian, Cassandra R. Zylstra, Daniel R. Robinson, Pradip Roy-Burman, Aubie K. Shaw, Bree D. Buckner-Berghuis, Robert E. Sigler, James H. Resau, Ruth Sullivan, Wade Bushman, and Bart O. Williams. 2007. Inactivation of Apc in the mouse prostate causes prostate carcinoma. Cancer Research 67(6): 2490–2496. Qian, Chao-Nan, James H. Resau, and Bin Tean Teh. 2007. Prospects for vasculature reorganization in sentinel lymph nodes. Cell Cycle 6(5): 514–517. Wallar, Bradley J., Aaron D. DeWard, James H. Resau, and Arthur S. Alberts. 2007. RhoB and the mammalian Diaphanousrelated formin mDia2 in endosome trafficking. Experimental Cell Research 313(3): 560–571. Zhang, Y.-W., B. Staal, Y. Su, P. Swiatek, P. Zhao, B. Cao, J. Resau, R. Sigler, R. Bronson, and G.F. Vande Woude. 2007. Evidence that MIG-6 is a tumor-suppressor gene. Oncogene 26(2): 269–276. Moshitch-Moshkovitz, Sharon, Galia Tsarfaty, Dafna W. Kaufman, Gideon Y. Stein, Keren Shichrur, Eddy Solomon, Robert H. Sigler, James H. Resau, George F. Vande Woude, and Ilan Tsarfaty. 2006. In vivo direct molecular imaging of early tumorigenesis and malignant progression induced by transgenic expression of GFP-Met. Neoplasia 8(5): 353–363. Qian, Chao-Nan, Bree Berghuis, Galia Tsarfaty, MaryBeth Bruch, Eric J. Kort, Jon Ditlev, Ilan Tsarfaty, Eric Hudson, David G. Jackson, David Petillo, Jindong Chen, James H. Resau, and Bin Tean Teh. 2006. Preparing the “soil”: the primary tumor induces vasculature reorganization in the sentinel lymph node before the arrival of metastatic cancer cells. Cancer Research 66(21): 10365–10376. Tsarfaty, Galia, Gideon Y. Stein, Sharon Moshitch-Moshkovitz, Dafna W. Kaufman, Brian Cao, James H. Resau, George F. Vande Woude, and Ilan Tsarfaty. 2006. HGF/SF increases tumor blood volume: a novel tool for the in vivo functional molecular imaging of Met. Neoplasia 8(5): 344–352. Yao, Xin, Chao-Nan Qian, Zhong-Fa Zhang, Min-Han Tan, Eric J. Kort, James H. Resau, and Bin Tean Teh. 2006. Two distinct types of blood vessels in clear cell renal cell carcinoma have contrasting prognostic implications. Clinical Cancer Research 13(1): 161–169. .

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