Xiao-Ming Yin, M.D., Ph.D. Dr. Yin is Professor and the Associate Director of the Division of Molecular Diagnostics and is a member of several graduate programs (CMP, CATER, MSTP and PIMB). Click here for Dr. Yin's biosketch. Office Location: Division of Molecular Diagnostics Department of Pathology 7th Floor Scaife Hall, Room S739 3550 Terrace Street Pittsburgh, PA 15261 Lab Address Scaife Hall S736, S745 Contact Information: Office Phone: (412) 648-8436 Laboratory Phone:(412) 648-8067 Fax: (412) 648-9564 E-mail: xmyin@pitt.edu Research Interests: Our laboratory is interested in elucidating the molecular mechanisms of cell death and cell survival mechanisms, particularly autophagy and apoptosis, in the context of cancer therapy, tissue injury and metabolic disturbance for the purpose of understanding the fundamental biological significance and developing novel therapeutic approaches. 1. Mechanisms of autophagy and apoptosis in cancer therapy We have been working on the cell death/cell survival mechanism in the response of cancer cells to therapeutic agents. We are particularly interested in the mechanism of autophagy, a conserved cellular process activated in stress condition to protect cells, and its interaction with the apoptosis machinery in determining the outcome of cancer cells to therapeutic agents. Specifically, we have defined the importance of the cross-relationship of proteasome, autophagy and endoplasmic reticulum. . Our major findings include that autophagy could be activated in response to proteasome inhibition, which is mediated by ER stress. We have further defined that autophagy plays a protective effect in cancer cells in response to proteasome inhibitors or ER function inhibitors, both are cytotoxic agents. As a result, suppressing autophagy in this setting leads to an enhanced cell death. Intriguingly, such a combination of ER stress inducers/proteasome inhibitor with autophagy inhibitors has little effects on non-transformed cells. Thus this combination may provide a novel therapeutic strategy to treat cancer cells selectively without increasing the harm to the normal cells. We are continuing our work on both the fundamental mechanism of autophagy and its applications in cancer therapy. 2. Mechanisms of apoptosis and autophagy in liver injury and metabolic disturbance We have been interested in the regulation of apoptosis by Bcl-2 family proteins at the mitochondrial level and how this regulation interacts with various signaling pathways. An example of how we approach the question is illustrated in a murine model of hepatocyte injury, which is initiated by the Fas/TNF-R1 stimulation Over the years, we have defined both Bid-dependent and Bid-independent mitochondria activation pathways. The latter is related to the activation of JNK and ROS. We have also characterized that Bid could activate mitochondria via multiple mechanisms involving the oligomerization of Bax and Bak, cristae reorganization, generation of reactivate oxygen species, opening of mitochondrial permeability transition pore. Recent work showed that autophagy is important in the development of tissue injury to a variety of insults . Our ongoing work in liver injury has also defined that autophagy could play a significant role and modulating autophagy in those settings could greatly affected the outcome. We are applying our expertise in both autophagy and apoptosis in studying the mechanisms involved. Selected Publications: Yin, X-M. Bid, a BH3-only multi-functional molecule, is at the cross road of life and death. Gene, 369: 7-19, 2006. Chen, X, W-X, Ding, H-M. Ni, W. Gao, Y-H Shi, A. A. Gambotto, J. Fan, A.A. Beg and X-M. Yin. Bid-independent mitochondria activation in TNF -induced apoptosis and liver injury. Mol. Cell. Bio. 27 (2): 541-553, 2007. Ding, W-X, H-M. Ni, W. Gao, Y-F. Hou, M. A Melan, X. Chen, D. B. Stolz, Z.-M. Shao and X-M. Yin. Differential effects of endoplasmic reticulum stress induced-autophagy on cell survival. J. Bio. Chem. 282: 4702-4710, 2007. Ding, W-X, H-M. Ni, X. Chen, J. Yu, L. Zhang and X.-M. Yin. A coordinated action of Bax, PUMA and p53 promotes MG132-induced mitochondria activation and apoptosis in colon cancer cells. Mol. Cancer Ther., 6:1062-1069, 2007. Feng, R, H.-M. Ni, S. Y. Wang, I. L. Tourkova, M.R. Shurin, H. Harada and X.-M. Yin. Cyanidin-3-rutinoside, a natural polyphenol antioxidant, selectively kills leukemic cells by induction of oxidative stress. J. Bio. Chem.,282: 13468-13476, 2007. Ding, W-X, H-M. Ni, W. Gao, T. Yoshimori, D.B. Stolz, D. Ron and X-M. Yin. Linking of autophagy to ubiquitin proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Amer. J. Path. 171: 513-524, 2007. Zhao, Y, D. DiFrancesca, X. Wang, R. Zarnegar, G. Michalopoulos and X. M. Yin. Promotion of Fas-mediated Apoptosis in Type II Cells by High Doses of Hepatocyte Growth Factor Bypasses the Mitochondrial Requirement. J. Cell Physio., 213: 556-563, 2007. Ding, W-X, H-M. Ni and X-M. Yin. Absence of Bax Switched MG132-induced Apoptosis to Non-Apoptotic Cell Death that Could be Suppressed by Transcriptional or Translational Inhibition. Apoptosis 12: 2233-2244, 2007 Yin, X.-M. Bid. in Encyclopedia of Cancer (2nd Edition. Ed. by Manfred Schwab), Springer, 2007. Ni, H-M., X. Chen, L. Chen, D. DiFrancesca, H. Harada and X-M. Yin. The impact of genetic background and Bid on the phenotype of Bcl-2 deficiency in mice. Apoptosis 13: 53-62, 2008 Gao, W, W-X. Ding, D. B. Stolz and X.-M. Yin. Macroautophagy induced by exogenously introduced calcium. Autophagy 4(6): 1-8, 2008 Shi, Y-H., W.-X. Ding, J. Zhou, J.-Y. He, Y. Xu; A. Gambotto, H. Rabinowich, J. Fan and X.-M. Yin. Expression of X-linked inhibition-of-apoptosis protein in hepatocellular carcinoma promotes metastasis and predicts tumor recurrence. Hepatology 48:497-507, 2008. Ding, W-X and X.-M. Yin. Sorting, recognition and activation of the misfolded protein degradation pathways through autophagy and the proteasome. Autophagy 4(2): 141-150, 2008 Yin, X.-M. W-X. Ding and W. Gao. Autophagy in the liver. Hepatology 47:1773-1785, 2008 Ni, H-M., X. Chen, W-X. Ding, M. Schuchmann and X-M. Yin. Differential roles of JNK in ConA/GalN and ConA-induced liver injury in mice. Am. J. Pathology 173:962-972, 2008 Ni, H-M, X. Chen, Y-H. Shi, Y. Liao, A.A. Beg, J. Fan, X-M. Yin. Genetic delineation of the pathways mediated by Bid and JNK in TNF -induced liver injury in adult and embryonic mice. J Biol Chem. 284: 4373-4382, 2009 Ding, W-X, H-M Ni, W. Gao, X. Chen, J.H. Kang, D. B. Stolz, J. Liu and X.-M. Yin. Oncogenic transformation confers a selective susceptibility to the combined suppression of the proteasome and autophagy. Mol Cancer Ther. 8: 2036, 2009 W-X. Ding and X.-M. Yin. Analysis of autophagy in the liver and hepatocytes. Methods in Enzymology, 453: 391-410, 2009.