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Research Interests:
Our laboratory is interested in elucidating the molecular mechanisms of cell death and cell survival mechanisms in the context of tissue injury and cancer biology for the purpose of understanding the fundamental biological significance and developing novel therapeutic approaches.
1. Activation of the mitochondria apoptosis pathway in liver injury
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 1)  . This extrinsic stimulus normally would bypass the control of Bcl-2 family proteins, as the later are mainly for the intrinsic pathway. However, in the liver, a unique Bcl-2 family protein, Bid, is required for the effective killing. Bid is activated by post-translational proteolysis that leads to its translocation from the cytosol to the mitochondria. Thus Bid connects the two pathways and subjects the extrinsic activation of caspases under the control of the intrinsic pathways in this setting. We have characterized this pathway and defined the key step in the death receptor pathway that needs the mitochondria assistance. Thus Bid-induced Smac release from the mitochondria is important to revoke XIAP-mediated repression of caspase activation. We have further demonstrated that when the caspase-8 activation is augmented by additional agents this requirement for mitochondria participation could be bypassed.
We have defined 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 (Figure 2)  . There could be additional events, such as mitochondria fission/fusion that would need to be defined.
We have recently also characterized a mitochondria pathway that is independent of Bid. Bid-deficient mice can be still rendered to death receptor induced apoptosis in the liver, if the stimulation is TNF . This cytokine can induce a delayed but nevertheless severe liver injury in the bid-deficient mice in the presence of a liver-specific transcription inhibitor, D-galactosamine, which blocks NF- B activation. Furthermore, bid-deficiency could not rescue the lethal phenotype of NF-kB defective mice (RelA-deletion), which is caused by TNF toxicity. Mitochondria death pathway could be activated in this status as well. We have found that ROS, JNK and Bid-independent activation of Bax and Bak could be all part of the mechanisms leading to the mitochondria activation (Figure 3)  .
2. Mechanisms of autophagy and its significance in cancer therapy
We have been also 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 4)  . 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.
Selected Publications:
- Kim, T-H, Y. Zhao, W.-X. Ding, J. N. Shin, X. He, Y.-W. Seo, J. Chen, H. Rabinowich, A. A. Amoscato and X.-M. Yin. Bid-cardiolipin interaction at mitochondrial contact site contributes to mitochondrial cristae reorganization and cytochrome c release. Mol Biol. Cell 15:3061-3072, 2004.
- Ding, W-X, H.-M. Ni, D. DiFrancesca, D. B. Stolz and X.-M. Yin. Bid-dependent mitochondrial generation of oxygen radicals alters mitochondrial structures and functions following death receptor activation. Hepatology 40: 403-413, 2004.
- Ding, W.-X. and X.-M. Yin. Dissection of the multiple mechanisms of TNF -induced apoptosis in liver injury. J. Cell. Mol. Med. 8(4): 445-454, 2004.
- Yin, X-M and G. P. Linette. Programmed cell death and breast cancer. In "Molecular Oncology of Breast Cancer" (ed. J. S. Ross and G. N. Hortobagyi), Chapter 21, Jones and Bartlett Publishers, 2005.
- Li, B., H.-M. Ni, X. Chen, D. DiFrancesca and X.-M. Yin. Deletion of Bid impedes cell proliferation and hepatic carcinogenesis. American J. Path. 166:1523-1532, 2005.
- 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.
- Jiang, M, N. Pabla, R. F. Murphy, T. Yang, X.-M. Yin, K. Degenhardt, E. White, and Z. Dong. Nutlin-3 protects kidney cells during cisplatin therapy by suppressing Bax/Bak activation. J. Bio. Chem. 282: 2636-2645, 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.
- 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, 2007 (published on line July 9, 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.
- Yin, X.-M. Bid. in Encyclopedia of Cancer (2nd Edition. Ed. by Manfred Schwab), Springer, 2007.
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