Xiao-Ming Yin, MD, PhD
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. (Figure 1). 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.
Our present focus is to understand why autophagy is particularly important for cancer cells to survive and how this knowledge could be translated to novel cancer therapy in the clinical setting.
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 (Figure 2). 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 (Figure 3). Our ongoing work in liver injury has also defined that autophagy could play a significant role and modulating autophagy in the setting of alcoholic and non-alcoholic steatohepatitis could greatly affected the outcome. We are applying our expertise in both autophagy and apoptosis in studying the mechanisms involved in the pathogenesis and developing potential therapeutic approaches.
3. Basic mechanisms of apoptosis, autophagy and cell proliferation
Along the studies of cell death and cell survival in tissue injury and cancer biology, we also investigated the basic mechanisms involved in these processes. We are particularly interested in 1) how Bid, a BH3-only Bcl-2 family proteins regulate cell death and cell proliferation, 2) how mitochondria are involved in cell death and cellular homeostasis via the crosstalk the apoptosis and autophagy pathways, 3) how basic autophagy machinery is activated and 4) how this machinery could be modulated pharmacologically for the benefits of treating diseases.
Ongoing work in these areas have resulted in interesting findings and established some novel paradigms that connect different signaling pathways together. For example, Bid links the death receptor apoptosis pathway to the mitochondria apoptosis pathway; Bid is not only important for apoptosis, but also for cell proliferation; the two cellular degradation pathways, the proteasome and the lysosome are functionally connected via ER stress; Mitochondria ROS generation is required for the activation of both apoptosis and autophagy, and etc. We anticipate that more of such interesting findings will continuously come up from this line of research.
Recent Publications from Our Laboratory
Apoptosis and Autophagy in Liver Injury
•1. 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.
PubMed Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1800794/
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•2. 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 Physiol, 213: 556-563, 2007.
PubMed Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2636794/
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•3. 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.
PubMed Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2543065/
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•4. 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
PubMed Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2640960/
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•5. Ding, W.-X., M. Li, X. Chen, H-M. Ni, W. Gao, B. Lu, D. B. Stolz, D. L. Clemens and X.-M. Yin. Mitigation of acute ethanol-induced hepatotoxicity and steatosis by autophagy. Gastroenterology, July 23, 2010 (Epub ahead of print)
Apoptosis and Autophagy in Cancer Biology and Therapy
•1. 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.
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•2. 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 (Cover Story)
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•3. 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
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•4. 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
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•5. 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.
PubMed Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768766/
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•6. 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
PubMed Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2711219/
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•7. Feng, R., S. Y. Wang, Y.H. Shi, J. Fan and X.-M. Yin. Delphinidin induces necrosis in hepatocellular carcinoma cells in the presence of 3-methyladenine, an autophagy inhibitor. J. Agric Food Chem. 58: 3957, 2010
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Basic Mechanisms of Apoptosis, Autophagy and Cell Proliferation
•1. 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.
PubMed Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1934546/
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•2. 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
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•3. Gao, W, W-X. Ding, D. B. Stolz and X.-M. Yin. Induction of macroautophagy by exogenously introduced calcium. Autophagy, 4(6): 1-8, 2008.
PubMed Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2696695/
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•4. Yin, X.-M. W-X. Ding and W. Gao. Autophagy in the liver. Hepatology 47:1773-1785, 2008
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•5. 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
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•6. Ding, W.-X. and Yin, X.-M. Bcl-2 family proteins. In "Essentials of Apoptosis: A Guide for Basic and Clinical Research" (2nd ed. edited by Xiao-Ming Yin and Zheng Dong), pp. 25-62, Springer, July 2009.
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•7. Gao, W., J.-H. Kang, Y. Liao, M. Li and Yin, X.-M. Autophagy and cell death. In "Essentials of Apoptosis: A Guide for Basic and Clinical Research" (2nd ed. edited by Xiao-Ming Yin and Zheng Dong), pp671-690, Springer, July 2009.
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•8. W-X. Ding and X.-M. Yin. Analysis of autophagy in the liver and hepatocytes. Methods in Enzymology, 453: 391-410, 2009.
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•9. Ni, H-M, C. J. Baty, N. Li, W-X. Ding, W. Gao, M. Li, X. Chen, J. Ma, G. K. Michalopoulos and X.-M. Yin. Bid regulates murine hepatocyte proliferation by controlling ER calcium homeostasis. Hepatology, 52: 338-348, 2010
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•10. Gao, W., J.-H. Kang, Y. Liao, W.-X. Ding, A. A. Gambotto, S. C. Watkins, Y.-J. Liu, D. B. Stolz and X.-M. Yin. Biochemical Isolation and Characterization of the Tubulovesicular LC3-positive Autophagosomal Compartment. J. Bio. Chem. 285: 1371-1383, 2010.
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•11. Ding, W.-X., H.-M. Ni, M. Li, Y. Liao, X. Chen, D. B. Stolz, G. W. Dorn II and X.-M. Yin. Nix is critical to two distinct phases of mitophagy: reactive oxygen species (ROS)-mediated autophagy induction and Parkin-ubiquitin-p62-mediated mitochondria priming. J. Bi. Chem. June 23, 2010 (E pub ahead of print)
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Books on Apoptosis
•1. "Essentials of Apoptosis: A Guide for Basic and Clinical Research" (1sr edition, by Xiao-Ming Yin and Zheng Dong), 259 pages, Humana Press, March 2003 (ISBN: 1-58829-146-4)
•2. "Essentials of Apoptosis: A Guide for Basic and Clinical Research" (2nd edition, by Xiao-Ming Yin and Zheng Dong), 740 pages, Springer-Human Press, June 2009. (ISBN: 978-1-60327-380-0)
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For a complete list of bibliography click here
