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Xiao-Ming Yin, MD, PhD

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Recent Publications from Yin's Laboratory

Current Research Interests:

1. Signaling regulation of autophagy in liver pathogenesis under metabolic stress

1). In exploring the role of autophagy in liver pathogenesis (Yin et al, Hepatology 2008; Ding et al, Methods in Enzymology 2009; Czaja et al, Autophagy, 2013), we have found that autophagy protects against ethanol-induced liver injury (Ding et al, Gastroenterology 2010; Lin et al, J. Hepatology 2013).  This leads to the discovery that ethanol-induced autophagy is highly selective toward mitochondria and lipid droplets.  While selective autophagy had been well defined in cultured cells this is the first in vivo evidence that such events occur in a pathologically relevant context.  We will determine the signaling pathway and examine the hypothesis that autophagy may protect against AFLD by selectively removal of damaged mitochondria and lipids to prevent ROS generation and lipid peroxidation, which are major insults causing liver injury.

 

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2). Recent studies in our laboratory also suggest that autophagy and the related signaling pathways are disturbed in non-alcohol fatty liver disease (NAFLD) and restoration of these events could be beneficial to the control of NAFLD (Lin et al, J. Hepatology 2013).  We are investigating the mechanistic relationship of nutrient signaling, autophagy activation and lysosome degradation using both in vitro cellular model and in vivo animals models (Li et al, J. Biol. Chem 2013).

3). We are also examining the mechanistic relationship between autophagy and liver injury.  Autophagy is required to maintain hepatocyte homeostasis and deficiency of autophagy leads to hepatomegaly, inflammation, fibrosis and tumor formation.  It is not known how the pathogenesis was developed and we are investigating this issue actively.

 

 

2. Mitochondrial dynamics and mitophagy

We have found that autophagic degradation of mitochondria, or mitophagy, can be defined in two stages, the mobilization of autophagy machinery and the recognition of the mitochondria being removed (Ding et al, J Bio Chem 2010, Ding and Yin, Biol Chem, 2012).  We have determined that distinct mechanisms can be involved in the two phases.

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This approach has clarified the confusion on this subject in the field regarding which mechanisms, and why they are involved in mitophagy.  Furthermore by studying the role of autophagy in alcohol-induced liver damage we defined mitophagy in this disease context (Ding et al, Gastroenterology 2010), which provides a new model for our study. 

We have also determined connections between mitochondrial fission/fusion dynamics, mitophagy and a new form of dynamics, mitochondrial spheroid formation (Ding et al, J. Bio Chem, 2012a and 2012b; Yin and Ding, Autophagy, 2013).  These events are reciprocally regulated by Parkin/PARK2 and mitofusins.

 

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We showed for the first time that mitochondrial spheroids represent a mitochondrial dynamics that involves a 3-dimensional transformation.

 

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The pathological significance of these mitochondrial dynamics will be explored in the context of liver injury.

 

 

3. Mechanisms of autophagy in cell death and cancer therapy

Our major contributions to, and interests in, the field are as follows:

1). We have defined the first mechanistic link as the endoplasmic reticulum stress between the lysosome-based autophagic degradation and the proteasome-based ubiquitinated protein degradation, the two major cellular degradation system (Ding et al, J Biol Chem, 2007; Amer J Path, 2007; Mol Cancer Ther, 2007; Autophagy, 2008).

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Thus, suppression of proteasome activates autophagy via ER stress-mediated IRE-1-JNK1 pathway and direct disturbance of ER homeostasis activates autophagy as well. 

2). In this context, autophagy serves as a protective mechanism against cell death, thus reducing the efficacy of proteasome inhibitors, such as Bortezomib, in killing cancer cells.  The combined use of autophagy inhibitors overcomes the protection, enhancing cancer therapy (Ding et al, Amer J Path, 2007; Mol Cancer Ther, 2009). 

3). We were the first to define that transformed cancer cells, but not normal or immortalized non-transformed cells, mostly depend on the protection conferred through autophagy (Ding, et al, Mol Cancer Ther, 2009; BBRC, 2012).  This provides yet another important rationale in applying autophagy inhibitors in cancer therapy, i.e., to increase the specificity of the therapy toward cancer cells. 

4) Our other contributions to autophagy field include the development of novel chemical biology approaches for autophagy modulators and the development of novel assays (Li et al, J. Bio. Chem 2011 and 2013; Li et al, Autophagy 2012)

 

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Recent Publications from Yin’s Laboratory

For a complete list of bibliography click here


 

Books on Apoptosis

“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)
Cover Image

 

“Cell Death in Biology and Diseases”, a series devoted to the topics of cell death (edited by Xiao-Ming Yin and Zheng Dong), Humana-Springer
Vol 1: Cell Death Signaling in Cancer Biology: Opportunities and Approaches for Therapeutic Intervention (volume editor: Daniel E. Johnson, 2013, ISBN: 978-1-4614-5846-3);
Front Matter

 

2015

Li, M., Z. Yang, L.L. Vollmer, Y. Gao, Y. Fu, C. Liu, Xiaoyun Chen, P. Liu, A. Vogt, X.-M. Yin.  AMDE-1 Is a Dual Function Chemical for Autophagy Activation and Inhibition.  PLoS One 10 (3): e0122083, April 20, 2015 (doi: 10.1371/journal.pone.0122083).
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2014

Chen, X., B. Khambu, H. Zhang, W. Gao, M. Li , Xiaoyun Chen, T. Yoshimori, X.-M. Yin. Autophagy induced by calcium phosphate precipitates targets damaged endosomes. J Biol Chem. 289: 11162-11174, 2014
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Gallo, L.I., Y. Liao, W.G. Ruiz, D. R. Clayton, M. Li, Y.-J. Liu, Y. Jiang, M. Fukuda, G. Apodaca, and X.-M. Yin.  TBC1D9B functions as a GTPase-activating protein for Rab11a in polarized MDCK cells, Mol Biol. Cell.  25: 3779-3797, 2014
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2013

Lin, C.-W., H. Zhang, M. Li, X. Xiong, Xi Chen, X. Chen, C. X. Dong, and X.-M. Yin. Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice.  J. Hepatology, 58: 993-999, 2013 (Expert Comment on 58: 845-846, 2013 )
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Chen, D., Xi Chen, M. Li, H. Zhang, W.-X. Ding and X.-M. Yin. CCCP-induced LC3 lipidation depends on Atg9 whereas FIP200/Atg13 and Beclin 1/Atg14 are dispensable.  Biochemical and Biophysical Research Communications, 432: 226-230, 2013
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Li M, B. Khambu, H. Zhang, JH, Kang, Xiaoyun Chen, D. Chen, L. Vollmer L, P.Q. Liu, A. Vogt, X.-M. Yin.  Suppression of lysosome function induces autophagy via a feedback downregulation of MTORC1 activity.  J. Biol. Chem.  288: 35769-35780, 2013.
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Czaja, M. J., W.-X. Ding, T. M. Donohue, Jr. S. L. Friedman, J.-S. Kim, M. Komatsu, J. J. Lemasters, A. Lemoine, J. Lin, J. J. Ou, D. H. Perlmutter, G. Randall, R.B. Ray, A. Tsung,  and X.-M. Yin.  Autophagy in the liver.  Autophagy. 9:1131-1158, 2013.
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Yin, X.-M. and W.-X. Ding.  The reciprocal roles of PARK2 and mitofusins in mitophagy and mitochondrial spheroid formation.  Autophagy, 9: 1687-1692, 2013
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Zinkel, S. S., X.-M. Yin and A. Gross. Rejuvenating Bi(d)ology.  Oncogene, 32: 3213-3219, 2013
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2012

Li, M., Xi Chen, Q.-Z. Ye, A. Vogt and X.-M. Yin.  A High-throughput FRET-based Assay for Determination of Atg4 Activity.  Autophagy, 8:401-412, 2012
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Ding, W.X., Xi Chen, and X.-M. Yin.  Tumor cells can evade dependence on autophagy through adaptation.  Biochemical and Biophysical Research Communications.  425: 684-688, 2012
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Chen, Xi, M. Li, D. Chen, W. Gao, J.L. Guan, M. Komatsu and X.-M. Yin.  Autophagy induced by calcium phosphate precipitates involves endoplasmic reticulum membranes in autophagosome biogenesis.  PLoS One 7(12): e52347, 2012
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Ding, W-X., M. Li, J.M. Biazik, D.G. Morgan, F. Guo, H-M. Ni, M. Goheen, E-L.Eskelinen, and X-M. Yin. Electron microscopic analysis of a phagosome-like mitochondrial structure.  J. Biol. Chem.  287: 42373-42378, 2012
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Ding, W-X., F. Guo, H-M. Ni, A. Bockus, S. Manley, D.B. Stolz, E-L. Eskelinen, H. Jaeschke and X.-M. Yin.  Parkin and mitofusins reciprocally regulate mitophagy and mitochondrial phagosome formation.  J. Biol. Chem.  287:42379-42388, 2012
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Ding, W.-X. and X.-M. Yin.  Mitophagy: mechanisms, pathophysiological roles and analysis.  Biol Chem.  393: 547-564, 2012
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2011

Ni, H.-M., A. Bockus, A. L. Wozniak, K. Jones, S. Weinman, X.-M. Yin and W-X. Ding.  Dissecting the dynamic turnover of GFP-LC3 in autolysosomes.  Autophagy 7: 54-70, 2011
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Li, M., Y. Hou, J. Wang, X. Chen and X.-M. Yin.  Kinetics comparisons of mammalian Atg4 homologues indicate selective preferences toward diverse Atg8 substrates.  J. Bio. Chem. 286:7327-7338, 2011
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Kang, J.-H., M. Li, X. Chen, and X.-M. Yin.  Proteomics analysis of starved cells revealed Annexin A1 as an important regulator of autophagic degradation.  Biochemical and Biophysical Research Communications.  407:581-586, 2011
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Shen, H., H. Yu, P.H. Liang, R. Xu Feng, Y. Song, X. Hu, X. Chen, X.-M. Yin and T. Cheng.  Bid, a BH3-only Bcl-2 family protein, is a positive regulator for lymphoid cell regeneration at multiple key maturation steps.  Experimental Hematology. 39: 947-957, 2011
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Shi, Y-H, J. Fan, Chih-Wen Lin, W-X Ding and X.-M. Yin.  Macroautophagy.  In “Molecular Pathology of Liver Diseases”  (Ed by Satdarshan P. S. Monga), Springer, 2011
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Chen, X. and X.-M. Yin.  Coordination of autophagy and the proteasome in resolving endoplasmic reticulum stress.  Veterinary Pathology, 48: 245-253, 2011
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2010

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 139: 1740-1752, 2010
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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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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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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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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. Bio. Chem. 285: 27879-27890, 2010
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Shi, Y-H., J. Fan, Z.-B. Ding and X.-M. Yin.  Apoptosis in the liver.  In “Modern Insight into Disease from Molecules to Man”.  (Ed by Victor R. Preedy).  Science Publishers, 2010
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