Research Interests
Autophagy and Apoptosis in liver injury and cancer therapy; Redox Signaling and Mitochondrial damage;
1. Mechanisms of autophagy in alcoholic liver disease.
Macroautophagy (referred to as autophagy hereafter) is a major intracellular degradation system that is responsible for the degradation of long-lived proteins and other cellular contents. It is usually activated in response to adverse environment, such as the deprivation of nutrients or growth factors. Autophagy plays a role in development, in defending against microbial infections, in regulating lipid homeostasis and organelles turn over such as mitochondria, and in the pathogenesis of a number of diseases including cancer.
Alcohol abuse is a major cause of liver injury. The pathology of alcoholic liver disease develops over a prolonged period. However, the cellular defense mechanisms against the detrimental effects of alcohol are not well understood. The research work in this laboratory is to study whether autophagy could be a protective mechanism against ethanol toxicity. We are now studying the mechanisms of how ethanol induces autophagy and exploring potential therapeutic drugs for alcoholic diseases by inducing autophagy. We also interest in how autophagy would help to mitigate alcohol-induced fatty liver (steatosis) and non-alcoholic fatty liver (NASH).
2. Mechanisms of mitochondria autophagy (mitophagy)
Mitochondria are dynamic organelles that are responsible for creating more than 90% of the energy needed by the body. Mitochondria are also the central-regulators for apoptosis and the major sources for the production of reactive oxygen species. Many environmental toxicants and chemotherapeutic drugs can damage mitochondria. Damaged mitochondria have been involved in cell death, ischemia and reperfusion injury, aging and many neuro-degenerative conditions such as Alzheimer's and Parkinson's disease. It is thus important to eliminate damaged and aged mitochondria to protect the cells against its detrimental effects on the cells. It is now known that autophagy plays an important role to remove these damaged mitochondria, a process, called mitophagy. However, it is not know how damaged mitochondria are eventually recognized by the autophagosomes in mammalian cells although it has recently been reported that Atg32 is required for mitophagy in yeast. Our current research work is to study the molecular signals that could be involved in this process such as redox signaling and mitochondrial fission and fusion machinery.
3. Modulation of autophagy in cancer therapy
Bortezomib, a proteasome inhibitor, has been approved by FDA to treat refractory/relapsed multiple myeloma. We recently discovered that inhibition of proteasome that could induce autophagy, which served as a protective mechanism against cell death. Inhibition of autophagy greatly sensitized Bortezomib induced tumor cell death but had less effect on normal cells. We are interested in exploring the use of the combination of inhibition of autophagy with chemotherapeutic drugs in caner therapy.
Selected Publications
Ding, W.X., Shen, H.M. and Ong, C.N. (2000) The critical role of ROS and mitochondrial membrane permeability in microcystin-LR induced rapid apoptosis in primary rat hepatocytes. Hepatology 32:547-555.
Zhao, Y, Ding, W.X*, Qian T, Watkin S, Lemasters J.J. and Yin, X.M. (2003) Bid activates multiple mitochondrial apoptotic mechanisms in primary hepatocytes after death receptor engagement. Gastroenterology 125:854-67. *Co-first author.
Kim, T.H.*, Zhao, Y*, Ding, W.X*., Shin, J.N., He, X., Seo Y.W., Chen, J., Rabinowich H., Amoscato, A. and Yin, X.M. (2004) Bid-cardiolipin interaction at the mitochondria contact site contributes to mitochondria cristae reorganization. Mol Biol Cell. 15:3061-72. *Co-first author.
Ding, W.X, Ni, H.M., Defrancesca, D., Stolz, D.B., and Yin, X.M (2004) Bid-Induced Oxygen Radicals Promote Mitochondrial Dysfunction, Caspase Activation and Hepatocyte Apoptosis. Hepatology 40:403-413.
Chen X, Ding, W.X. Ni, H.M., Gao, W., Shi, Y.H., Gambotto, A.A., Fan, J., Beg, A.A. and Yin, X.M. (2007) Bid-independent Mitochondria Activation in TNF{alpha}-induced Apoptosis and Liver Injury. Mol Cell Biol. 27(2):541-53.
Ding, W.X. Ni, H.M., Gao, W., Hou, Y.F., Melan, M.A., Chen X, Stolz, D.B., Shao, Z.M., and Yin, X.M. (2007) Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival. J Biol Chem. 282(7):4702-10.
Ding, W.X., Ni, H.M, Chen, X., Yu, J., Zhang, L., and Yin, X.M. (2007) A coordinated action of Bax, PUMA, and p53 promotes MG132-induced mitochondria activation and apoptosis in colon cancer cells. Mol Cancer Ther. 6(3):1062-9. * Cover story.
Ding, W.X. Ni, H.M., Gao, W., Yoshimori, T., Stolz, D.B., Ron, D., and Yin, X.M. (2007) Linking of Autophagy to Ubiquitin-Proteasome System Is Important for the Regulation of Endoplasmic Reticulum Stress and Cell Viability. Am J Pathol. 171(2):513-24.
Ding, W.X*. Ni, H.M.,and Yin, X.M. (2007) Absence of bax switched MG132-induced apoptosis to non-apoptotic cell death that is suppressed by transcriptional and translational inhibitors. Apoptosis. 12(12):2233-44. * correspondence author.
Ding, W.X., and Yin, X.M. (2008) Sorting, recognition and activation of the misfolded protein degradation pathways through macroautophagy and the proteasome. Autophagy. 4(2):141-50.
Yin, X.M., Ding, W.X., and Gao, W. (2008) Autophagy in the liver. Hepatology. 47(5):1773-85. Review.
Shi, Y.H., Ding, W.X., Zhou, J., He, J.Y., Xu, Y., Gambotto, A.A., Rabinowich, H., Fan, J. and Yin, X.M. (2008) Expression of X-linked inhibitor-of-apoptosis protein in hepatocellular carcinoma promotes metastasis and tumor recurrence. Hepatology. 48(2):497-507.
Ni, H.M., Chen, X, Ding, W.X., Schuchmann, M., and Yin, X.M. (2008) Differential Roles of JNK in ConA/GalN and ConA-Induced Liver Injury in Mice. Am J Pathol. 173(4):962-72.
Ding, W.X., and Yin, X.M. (2009) Analyzing macroautophagy in hepatocytes and the liver. Methods Enzymol. 453: 397-416.
Ding, W.X. Ni, H.M., Gao, W., Chen, X., Kang, J.H., Stolz, D.B., Liu, J., and Yin, X.M. (2009) Oncogenic transformation confers a selective susceptibility to the combined suppression of the proteasome and autophagy. Mol Cancer Ther. 8(7):2036-45.
Contact Information
Wen-Xing Ding , Ph.D.
Assistant Professor
Department of Pharmacology, Toxicology and Therapeutics
The University of Kansas Medical Center
MS 1018
3901 Rainbow Blvd.
Kansas City, Kansas 66160
Phone: 913-588-9813
Fax: 913- 588-7501
Email: wxding@kumc.edu
Curriculum Vitae in PDF Format available.
A post-doctoral position is currently open to study the above projects.
Updated 8/24/09
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The University of Kansas Medical Center