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Shengyun  Fang
 

Shengyun Fang Ph.D.

Academic Title: Associate Professor
Primary Appointment: Physiology
Secondary Appointments: Biochemistry and Molecular Biology
Location: 725 W. Lombard St. N360
Phone: (410) 706-2220
Fax: (410) 706-8184
Lab: N361 and N368

Personal History:

EDUCATION
M.D, Anhui Medical University (Clinical Medicine)
Ph.D., University of Iowa School of Medicine (Mentor: Dr. Ramesh Bhalla)

PROFESSIONAL EXPERIENCE
Postdoctoral Fellow, University of Iowa School of Medicine (Mentor: Dr. James Christensen).
Postdoctoral Fellow, Research Fellow and Staff Scientist, National Cancer Institute (Mentor: Dr. Allan M. Weissman).

Research Interests:

The endoplasmic reticulum (ER) is the site for maturation of proteins destined for the secretory pathway. Failure in maturation during translation or due to pathogenic insults, such as oxidative stress, genetic mutation, and disturbance of calcium homeostasis, leads to production of misfolded proteins. If not removed, misfolded protein accumulation in the ER causes ER stress. The latter is involved in the development and/or progression of many devastating diseases, including cancer, diabetes, and many neurodegenerative diseases, such as Parkinson’s, Huntington’s, Alzheimer’s and Lou Gehrig's disease (ALS). The major focus of our research is to understand how misfolded proteins in the ER are eliminated by the ER-associated degradation (ERAD) pathway and the interplay between ERAD and neurodegenerative disease proteins.

We are also interested in developing technologies for research and screening for drugs targeting the ERAD and ubiquitin proteasome pathway. For example, dislocation or retrotranslocation of misfolded protein from the lumen of the ER to the cytosol is required for their degradation. We have recently established a novel assay, namely, dislocation-dependent reconstitute GFP (drGFP) assay that allows, for the first time, visualizing protein dislocation from the ER. We have also developed a fluorescent ubiquitin chain sensor (UCS) that enables visualization of K48-linked polyubiquitination in living cells and quantifying polyubiquitin chains in vitro. UCR is now being used for studying the regulation of ERAD substrate ubiquitination. These technologies are not only great tools for research but will also serve as platforms for high throughput drug screening.

Publications:

1. Fang, S., Wu, R., and Christensen, J. (1993). Intramucosal nerve cells in human small intestine. J Auton Nerv Syst 44, 129-136.

2. Fang, S., Christensen, J., Conklin, J. L., Murray, J. A., and Clark, G. (1994). Roles of Triton X-100 in NADPH-diaphorase histochemistry. J Histochem Cytochem 42, 1519-1524.

3. Fang, S., Ledlow, A., Murray, J. A., Christensen, J., and Conklin, J. L. (1994). Vasoactive intestinal contractor: localization in the opossum esophagus and effects on motor functions. Gastroenterology 107, 1621-1626.

4. Fang, S., and Christensen, J. (1994). Distribution of NADPH diaphorase in intramural plexuses of cat and opossum esophagus. J Auton Nerv Syst 46, 123-133.

5. Christensen, J., and Fang, S. (1994). Colocalization of NADPH-diaphorase activity and certain neuropeptides in the esophagus of opossum (Didelphis virginiana). Cell Tissue Res 278, 557-562.

6. Conklin, J. L., O’Meara, B. W., Murray, J. A., Fang, S., Clark, E. D., and Christensen, J. (1995). Effect of nitroblue tetrazolium on NO synthase and motor function of opossum esophagus. Dig Dis Sci 40, 2390-2397.

7. Fang, S., Thomas, R. M., Conklin, J. L., Oberley, L. W., and Christensen, J. (1995). Co-localization of manganese superoxide dismutase and NADH diaphorase. J Histochem Cytochem 43, 849-855.

8. Fang, S., and Christensen, J. (1995). Manganese superoxide dismutase and reduced nicotinamide adenine dinucleotide diaphorase colocalize in the rat gut. Gastroenterology 109, 1429-1436.

9. Christensen, J., Fang, S., and Rick, G. A. (1995). NADPH-diaphorase-positive nerve fibers in smooth muscle layers of opossum esophagus: gradients in density. J Auton Nerv Syst 52, 99-105.

10. Thomas, R. M., Fang, S., Leichus, L. S., Oberley, L. W., Christensen, J., Murray, J. A., Ledlow, A., and Conklin, J. L. (1996). Antioxidant enzymes in intramural nerves of the opossum esophagus. Am J Physiol 270, G136-42.

11. Cullen, J. J., Herrmann, B. M., Thomas, R. M., Fang, S., Murray, J. A., Ledlow, A., Christensen, J., and Conklin, J. L. (1997). The role of antioxidant enzymes in the control of opossum sphincter of Oddi motility. Am J Physiol 272, G1050-6.

12. Sharma, R. V., Fang, S., and Bhalla, R. C. (1997). Factors influencing adenovirus-mediated gene transfer to endothelial and vascular smooth muscle cells in vivo and in vitro. Recent Res Dev in Mol Biol 1, 41-49.

13. Fang, S., Sharma, R. V., and Bhalla, R. C. (1997). Endothelial nitric oxide synthase gene transfer inhibits platelet-derived growth factor-BB stimulated focal adhesion kinase and paxillin phosphorylation in vascular smooth muscle cells. Biochem Biophys Res Commun 236, 706-711.

14. Sharma, R. V., Tan, E., Fang, S., Gurjar, M. V., and Bhalla, R. C. (1999). NOS gene transfer inhibits expression of cell cycle regulatory molecules in vascular smooth muscle cells. Am J Physiol 276, H1450-9.

15. Fang, S., Sharma, R. V., and Bhalla, R. C. (1999). Enhanced recovery of injury-caused downregulation of paxillin protein by eNOS gene expression in rat carotid artery. Mechanism of NO inhibition of intimal hyperplasia? Arterioscler Thromb Vasc Biol 19, 147-152.

16. Lorick, K. L., Jensen, J. P., Fang, S., Ong, A. M., Hatakeyama, S., and Weissman, A. M. (1999). RING fingers mediate ubiquitin conjugating enzyme (E2)-dependent ubiquitination. Proc Natl Acad Sci U S A 96, 11364-11369.

17. Yang, Y., Fang, S., Jensen, J. P., Weissman, A. M., and Ashwell, J. D. (2000). Ubiquitin Protein Ligase Activity of IAPs and Their Degradation in Proteasomes in Response to Apoptotic Stimuli. Science 288, 874-877.

18. Fang, S., Jensen, J. P., Ludwig, R. L., Vousden, K. H., and Weissman, A. M. (2000). Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J Biol Chem 275, 8945-8951.

19. Fang, S., Ferrone, M., Yang, C., Jensen, J. P., Tiwari, S., and Weissman, A.M. (2001) The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum. Proc Natl Acad Sci U S A 98, 14422-14427.

20. Xie, Q., Guo, H., Dallman, G., Fang, S., Weissman, A.M., and Chua, NH. (2002). SINAT5 promotes ubiquitin-related degradation of NAC1 to attenuate auxin signals. Nature 419, 167-170.

21. Liang, J.S., Kim, T., Fang, S., Yamaguchi, J., Weissman, A.M., Fisher, E.A., Ginsberg, H.N. (2003) Overexpression of the tumor autocrine motility factor receptor gp78, a ubiquitin protein ligase, results in increased ubiquitinylation and decreased secretion of apolipoprotein B100 in HepG2 cells. J Biol Chem 278:23984-8.

22. Doong, H., Rizzo, K., Fang, S., Kulpa, V., Weissman, A.M., Kohn, E.C. (2003). CAIR-1/BAG-3 abrogates heat shock protein-70 chaperone complex-mediated protein degradation: accumulation of poly-ubiquitinated Hsp90 client proteins. J Biol Chem 278:28490-500.

23. Magnifico, A., Ettenberg, S., Yang, C., Mariano, J., Tiwari, S., Fang, S., Lipkowitz, S., Weissman, A.M. (2003). HECT E3s target Cbl RING finger E3s for proteasomal degradation. J Biol Chem 278:43169-77.

24. Chen, G., Bower, K.A., Ma, C., Fang, S., Thiele, C.J., and Luo, J. (2004) Glycogen synthase kinase 3beta (GSK3beta) mediates 6-hydroxydopamine-induced neuronal death. Faseb J. 18:1162-4

25. Davydov, I.V., Woods, D., Safiran, J.S., Oberoi1, P., Fearnhead, H.O., Fang, S., Jensen, J., Weissman, A.M., Kenten, J. and Vousden, K.H. (2004). Assay for ubiquitin ligase activity: high throughput screen for inhibitors of hdm2. J Biomol Screen 9: 695-703

26. Zhong, X., Shen, Y.X., Ballar, P., Apostolou, Agami, R., and Fang, S. (2004). AAA ATPase p97/VCP interacts with gp78, a ubiquitin ligase for ER-associated degradation. J Biol Chem 279: 45676-84

27. Gong W, Jiang Y, Wang L, Wei D, Yao J, Huang S, Fang, S., Xie K (2005). Expression of autocrine motility factor correlates with the angiogenic phenotype of and poor prognosis for human gastric cancer. Clin Cancer Res. 11(16):5778-83.

28. Vij N, Fang, S., Zeitlin PL (2006) Selective inhibition of ERAD rescues uF508-CFTR and suppresses IL8 levels: therapeutic implications. J Biol Chem. 281(25):17369-78

29. Liang, J., Yin, C., Doong, H., Fang, S., Peterhoff, C., Nixon, R.A., and Monteiro, M.J. (2006). Characterization of Erasin: A novel endoplasmic reticulum protein involved in promoting endoplasmic reticulum-associated protein degradation. J Cell Sci 119(Pt 19): 4011-24

30. Lu ZM, Jia YS, Wang SH, Fang, S., and Wu Q (2006). Significance of an ubiquitin ligase hHRD1 expressed in human breast carcinoma. Acta Anatomica Sinica. 37(6): 681-4.

31. Zhang J, Jiang Y, Jia Z, Li Q, Gong W, Wang L, Wei D, Yao J, Fang, S., Xie K (2006). Association of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer. Clin Exp Metastasis. 23(7-8):401-10.

32. Shen Y, Ballar P, Fang, S. (2006). Ubiquitin ligase gp78 increases solubility and facilitates degradation of the Z variant of alpha-1-antitrypsin. Biochem Biophys Res Commun. 349(4):1285-93.

33. Ballar P, Shen Y, Yang H, Fang, S. (2006). The role of a novel p97/valosin-containing protein-interacting motif of gp78 in endoplasmic reticulum-associated degradation. J Biol Chem. 281(46):35359-68.

34. Shen Y, Ballar P, Apostolou A, Doong H, Fang, S. (2007). ER stress differentially regulates the stabilities of ERAD ubiquitin ligases and their substrates. Biochem Biophys Res Commun. 352(4):919-24.

35. Yang H, Zhong X, Ballar P, Luo S, Shen Y, Rubinsztein DC, Monteiro MJ, Fang S (2007). Ubiquitin ligase Hrd1 enhances the degradation and suppresses the toxicity of polyglutamine-expanded huntingtin. Exp Cell Res. 313(3):538-50.

36. Ballar, P. Zhong, Y. Nagahama, M. Tagaya, M. Shen, Y. Fang, S. (2007). SVIP is an endogenous inhibitor of ER-associated degradation J Biol Chem. 282(47):33908-14

37. Apostolou A, Shen Y, Liang Y, Luo J, Fang, S. Armet, a UPR-upregulated protein, inhibits cell proliferation and ER stress-induced cell death. Exp Cell Res. 2008 Aug 1;314(13):2454-67.

38. Ballar P, Fang, S. Regulation of ER-associated degradation via p97/VCP-interacting motif. Biochem Soc Trans. 2008 Oct;36(Pt 5):818-22.

39. Xu K, Shimelis H, Linn DE, Jiang R, Yang X, Sun F, Guo Z, Chen H, Wei Li, Chen HG, Kong X, Melamed J, Fang, S., Zhen Xiao, Veenstra TD and Qiu Y. Regulation of androgen receptor transcriptional activity and specificity by RNF6. Cancer Cell. 15(4):270-82.  PMCID: PMC2848969

40. Herr RA, Harris J, Fang, S., Wang X, Hansen TH. Role of the RING-CH Domain of Viral Ligase mK3 in Ubiquitination of Non-Lysine and Lysine MHC I Residues. Traffic. 2009 Sep;10(9):1301-17.

41. Lim PJ, Danner R, Liang J, Doong H, Harman C, Srinivasan D, Rothenberg C, Wang H, Ye Y, Fang, S., Monteiro MJ. Ubiquilin and p97/VCP bind erasin, forming a complex involved in ERAD. J Cell Biol. 2009 Oct 19;187(2):201-17.  PMCID: PMC2768832

42. Yu YQ, Liu LC, Wang FC, Liang Y, Cha DQ, Zhang JJ, Shen YJ, Wang HP, Fang, S., Shen YX. Induction profile of MANF/ARMET by cerebral ischemia and its implication for neuron protection. J Cereb Blood Flow Metab. 2010 Jan;30(1):79-91.  PMCID: PMC2949098

43. Ballar P, Ors AU, Yang H, Fang, S. Differential regulation of CFTRDeltaF508 degradation by ubiquitin ligases gp78 and Hrd1. Int J Biochem Cell Biol. 2010, 42(1):167-73.

44. Yang H, Liu C, Zhong Y, Luo S, Monteiro MJ, Fang S (2010). Huntingtin Interacts with the Cue Domain of gp78 and Inhibits gp78 Binding to Ubiquitin and p97/VCP. Plos One, Jan 26, 5(1):e8905.  PMCID: PMC2811200

45. Airavaara M, Chiocco MJ, Howard DB, Zuchowski KL, Peränen J, Liu C, Fang S, Hoffer BJ, Wang Y, Harvey BK. Widespread cortical expression of MANF by AAV serotype 7: localization and protection against ischemic brain injury. Exp Neurol. 2010 Sep;225(1):104-13.  PMCID: PMC2925275

46. Rothenberg C, Srinivasan D, Mah L, Kaushik S, Peterhoff CM, Ugolino J, Fang S, Cuervo AM, Nixon RA, Monteiro MJ. Ubiquilin functions in autophagy and is degraded by chaperone-mediated autophagy. Hum Mol Genet. 2010 Aug 15;19(16):3219-32.  PMCID: PMC2908472

47. Jiang H, Jans R, Xu W, Rorke EA, Lin CY, Chen YW, Fang S, Zhong Y, Eckert RL. Type I transglutaminase accumulation in the endoplasmic reticulum may be an underlying cause of autosomal recessive congenital ichthyosis. J Biol Chem. 2010 Oct 8;285(41):31634-46.  PMCID: PMC2951236

48. Xu S, Peng G, Wang Y, Fang S, Karbowski M. The AAA-ATPase p97 is essential for outer mitochondrial membrane protein turnover. Mol Biol Cell. 2010 Dec 14. [Epub ahead of print].  PMCID: PMC3031461

49. Ke Z, Wang X, Liu Y, Fan Z, Chen G, Xu M, Bower KA, Frank JA, Li M, Fang S, Shi X, Luo J. Ethanol Induces Endoplasmic Reticulum Stress in the Developing Brain. Alcohol Clin Exp Res. 2011 Sep;35(9):1574-1583. doi: 10.1111/j.1530-0277.2011.01503.x. Epub 2011 May 20.

50. Dong G, Ferguson JM, Duling AJ, Nicholas RG, Zhang D, Rezvani K, Fang S, Monteiro MJ, Li S, Li XJ, Wang H. Modeling pathogenesis of Huntington's disease with inducible neuroprogenitor cells. Cell Mol Neurobiol. 2011 Jul;31(5):737-47. doi: 10.1007/s10571-011-9679-0. Epub 2011 Mar 31.

51. Ugolino J, Fang S, Kubisch C, Monteiro MJ. Mutant Atp13a2 proteins involved in parkinsonism are degraded by ER-associated degradation and sensitize cells to ER-stress induced cell death. Hum Mol Genet. 2011 Sep 15;20(18):3565-77. Epub 2011 Jun 10.  PMCID: PMC3159557

52. Wang Y, Ballar P, Zhong Y, Zhang X, Liu C, Zhang YJ, Monteiro MJ, Li J, Fang S. SVIP Induces Localization of p97/VCP to the Plasma and Lysosomal Membranes and Regulates Autophagy. PLoS One. 2011;6(8):e24478. Epub 2011 Aug 31.  PMCID: PMC3164199

53. Zhong Y, Wang Y, Yang H, Ballar P, Lee JG, Ye Y, Monteiro MJ, Fang S. Importin β interacts with the ER-associated degradation machinery and promotes ubiquitination and degradation of mutant {alpha}1-antitrypsin. J Biol Chem. 2011 Sep 30;286(39):33921-30.  PMCID: PMC3190800

54. Shen YX, Sun AM, Fang S, Feng LJ, Li Q, Hou HL, Liu C, Wang HP, Shen JL, Luo J, Zhou JN. Hrd1 facilitates tau degradation and promotes neuron survival. Curr Mol Med. 2012 Feb 1;12(2):138-52.

55. Liu L, Liu C, Zhong Y, Apostolou A, Fang S. ER stress response during the differentiation of H9 cells induced by retinoic acid. Biochem Biophys Res Commun. 2012 Jan 13;417(2):738-43.

56. Liu A, Gong P, Hyun SW, Wang KZ, Cates EA, Perkins D, Bannerman DD, Puché AC, Toshchakov VY, Fang S, Auron PE, Vogel SN, Goldblum SE. TRAF6 Protein Couples Toll-like Receptor 4 Signaling to Src Family Kinase Activation and Opening of Paracellular Pathway in Human Lung Microvascular Endothelia. J Biol Chem. 2012 May 11;287(20):16132-45. Epub 2012 Mar 23.  PMCID: PMC3351307

57. Xu M, Chen G, Fu W, Liao M, Frank JA, Bower KA, Fang S, Zhang Z, Shi X, Luo J. Ethanol disrupts vascular endothelial barrier: implication in cancer metastasis. Toxicol Sci. 2012 May;127(1):42-53.  PMCID: PMC3327869

58. Zhong Y, Fang S. Live Cell Imaging Of Protein Dislocation From The Endoplasmic Reticulum. J Biol Chem. 2012 Aug 10;287(33):28057-66.  PMCID: PMC3431711

59. Chen Z, Du S, Fang S. gp78: a multifaceted ubiquitin ligase that integrates a unique protein degradation pathway from the endoplasmic reticulum. Curr Protein Pept Sci. 2012 Aug 1;13(5):414-24.