Huiyan Zeng, PhD

Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center
Phone: (617) 667-2329
Fax: (617) 667-3591


hzeng@bidmc.harvard.edu

Huiyan Zeng, PhD

Beth Israel Deaconess Medical Center

EDUCATIONAL TITLES

  • Assistant Professor, Medicine, Harvard Medical School
  • Assistant Professor, Medicine, Beth Israel Deaconess Medical Center

Research Abstract

The research in my laboratory focuses on the molecular mechanism and signaling pathways that regulate tumor angiogenesis. In gene profile studies of cultured endothelial cells exposed to VEGF-A165, we found that TR3 (mouse homologue, Nur77) was highly upregulated not only in VEGF-A165-stimulated endothelial cells, but also in microvessels in several examples of pathological angiogenesis in vivo, including adenovirus VEGF-A164-induced angiogenesis, skin wound healing and tumors. growth of B16 melanoma was completely inhibited in Nur77 knock out (nur77-/-) mice. Overexpression of TR3/Nur77 was sufficient by itself to induce angiogenesis and also that TR3/Nur77 had an essential role in VEGF-A165-induced angiogenesis.

Down syndrome candidate region 1 (DSCR1) is another gene that is identified to be upregulated by VEGF. DSCR1 can be expressed as four isoforms, one of which, isoform 4 (DSCR1-4), has recently been found to provide a negative feedback loop that inhibits VEGF-A165-induced endothelial cell proliferation in vitro and angiogenesis in vivo. We found that another DSCR1 isoform, DSCR1-1L, was also upregulated by VEGF-A165 in cultured endothelial cells and is strongly expressed in several types of pathological angiogenesis in vivo. Moreover, DSCR1-1L and DSCR1-4 were expressed in tumor microvascular structure, not in tumor cells, nor in normal vessel, either. DSCR1-1L, unlike DSCR1-4, potently activates angiogenesis and could be an attractive target for anti-angiogenesis therapy.

Another project is to study the role of protein kinase D in VEGF-induced angiogenesis. We demonstrate that PKD interacts with PLCg and becomes tyrosine phosphorylated upon VEGF stimulation, leading to PLCg activation and angiogenic response of VEGF-A165.

Publications

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  • Zhao S, Zhou L, Niu G, Li Y, Zhao D, Zeng H. Differential regulation of orphan nuclear receptor TR3 transcript variants by novel vascular growth factor signaling pathways. FASEB J. 2014. PubMed
  • Qin L, Zhao D, Xu J, Ren X, Terwilliger EF, Parangi S, Lawler J, Dvorak HF, Zeng H. The vascular permeabilizing factors histamine and serotonin induce angiogenesis through TR3/Nur77 and subsequently truncate it through thrombospondin-1. Blood 2013; 121:2154-64. PubMed
  • Chen X, Yang G, Song JH, Xu H, Li D, Goldsmith J, Zeng H, Parsons-Wingerter PA, Reinecker HC, Kelly CP. Probiotic yeast inhibits VEGFR signaling and angiogenesis in intestinal inflammation. PLoS ONE 2013; 8:e64227. PubMed
  • Ismail H, Mofarrahi M, Echavarria R, Harel S, Verdin E, Lim HW, Jin ZG, Sun J, Zeng H, Hussain SN. Angiopoietin-1 and vascular endothelial growth factor regulation of leukocyte adhesion to endothelial cells: role of nuclear receptor-77. Arterioscler Thromb Vasc Biol 2012; 32:1707-16. PubMed
  • Zhao D, Qin L, Bourbon PM, James L, Dvorak HF, Zeng H. Orphan nuclear transcription factor TR3/Nur77 regulates microvessel permeability by targeting endothelial nitric oxide synthase and destabilizing endothelial junctions. Proc Natl Acad Sci U S A 2011; 108:12066-71. PubMed
  • Liu X, Zhao D, James L, Li J, Zeng H. Requirement of the nuclear localization of transcription enhancer factor 3 for proliferation, migration, tube formation, and angiogenesis induced by vascular endothelial growth factor. FASEB J 2011; 25:1188-97. PubMed
  • Zhao D, Bakirtzi K, Zhan Y, Zeng H, Koon HW, Pothoulakis C. Insulin-like growth factor-1 receptor transactivation modulates the inflammatory and proliferative responses of neurotensin in human colonic epithelial cells. J Biol Chem 2011; 286:6092-9. PubMed
  • Zhao D, Desai S, Zeng H. VEGF stimulates PKD-mediated CREB-dependent orphan nuclear receptor Nurr1 expression: Role in VEGF-induced angiogenesis. Int J Cancer 2010. PubMed
  • Xiong Y, Huo Y, Chen C, Zeng H, Lu X, Wei C, Ruan C, Zhang X, Hu Z, Shibuya M, Luo J. Vascular endothelial growth factor (VEGF) receptor-2 tyrosine 1175 signaling controls VEGF-induced von Willebrand factor release from endothelial cells via phospholipase C-gamma 1- and protein kinase A-dependent pathways. J Biol Chem 2009; 284:23217-24. PubMed
  • An X, Jin Y, Guo H, Foo SY, Cully BL, Wu J, Zeng H, Rosenzweig A, Li J. Response gene to complement 32, a novel hypoxia-regulated angiogenic inhibitor. Circulation 2009; 120:617-27. PubMed
  • Liu X, Zhao D, Qin L, Li J, Zeng H. Transcription enhancer factor 3 (TEF3) mediates the expression of Down syndrome candidate region 1 isoform 1 (DSCR1-1L) in endothelial cells. J Biol Chem 2008; 283:34159-67. PubMed
  • Nagy JA, Benjamin L, Zeng H, Dvorak AM, Dvorak HF. Vascular permeability, vascular hyperpermeability and angiogenesis. Angiogenesis 2008; 11:109-19. PubMed
  • Zhao D, Zhan Y, Zeng H, Koon HW, Moyer MP, Pothoulakis C. Neurotensin stimulates expression of early growth response gene-1 and EGF receptor through MAP kinase activation in human colonic epithelial cells. Int J Cancer 2007; 120:1652-6. PubMed
  • Qin L, Zhao D, Liu X, Nagy JA, Hoang MV, Brown LF, Dvorak HF, Zeng H. Down syndrome candidate region 1 isoform 1 mediates angiogenesis through the calcineurin-NFAT pathway. Mol Cancer Res 2006; 4:811-20. PubMed
  • Qin L, Zeng H, Zhao D. Requirement of protein kinase D tyrosine phosphorylation for VEGF-A165-induced angiogenesis through its interaction and regulation of phospholipase Cgamma phosphorylation. J Biol Chem 2006; 281:32550-8. PubMed
  • Zhao D, Zhan Y, Zeng H, Moyer MP, Mantzoros CS, Pothoulakis C. Ghrelin stimulates interleukin-8 gene expression through protein kinase C-mediated NF-kappaB pathway in human colonic epithelial cells. J Cell Biochem 2006; 97:1317-27. PubMed
  • Zeng H, Qin L, Zhao D, Tan X, Manseau EJ, Van Hoang M, Senger DR, Brown LF, Nagy JA, Dvorak HF. Orphan nuclear receptor TR3/Nur77 regulates VEGF-A-induced angiogenesis through its transcriptional activity. J Exp Med 2006; 203:719-29. PubMed
  • Zhao D, Zhan Y, Zeng H, Koon HW, Moyer MP, Pothoulakis C. Neurotensin stimulates interleukin-8 expression through modulation of I kappa B alpha phosphorylation and p65 transcriptional activity: involvement of protein kinase C alpha. Mol Pharmacol 2005; 67:2025-31. PubMed
  • Zhao D, Zhan Y, Koon HW, Zeng H, Keates S, Moyer MP, Pothoulakis C. Metalloproteinase-dependent transforming growth factor-alpha release mediates neurotensin-stimulated MAP kinase activation in human colonic epithelial cells. J Biol Chem 2004; 279:43547-54. PubMed
  • Mukhopadhyay D, Zeng H, Bhattacharya R. Complexity in the vascular permeability factor/vascular endothelial growth factor (VPF/VEGF)-receptors signaling. Mol Cell Biochem 2004; 264:51-61. PubMed
  • Wang L, Zeng H, Wang P, Soker S, Mukhopadhyay D. Neuropilin-1-mediated vascular permeability factor/vascular endothelial growth factor-dependent endothelial cell migration. J Biol Chem 2003; 278:48848-60. PubMed
  • Zeng H, Zhao D, Yang S, Datta K, Mukhopadhyay D. Heterotrimeric G alpha q/G alpha 11 proteins function upstream of vascular endothelial growth factor (VEGF) receptor-2 (KDR) phosphorylation in vascular permeability factor/VEGF signaling. J Biol Chem 2003; 278:20738-45. PubMed
  • Zhao D, Kuhnt-Moore S, Zeng H, Wu JS, Moyer MP, Pothoulakis C. Neurotensin stimulates IL-8 expression in human colonic epithelial cells through Rho GTPase-mediated NF-kappa B pathways. Am J Physiol Cell Physiol 2003; 284:C1397-404. PubMed
  • Ratts R, Zeng H, Berg EA, Blue C, McComb ME, Costello CE, vanderSpek JC, Murphy JR. The cytosolic entry of diphtheria toxin catalytic domain requires a host cell cytosolic translocation factor complex. J Cell Biol 2003; 160:1139-50. PubMed
  • Zeng H, Datta K, Neid M, Li J, Parangi S, Mukhopadhyay D. Requirement of different signaling pathways mediated by insulin-like growth factor-I receptor for proliferation, invasion, and VPF/VEGF expression in a pancreatic carcinoma cell line. Biochem Biophys Res Commun 2003; 302:46-55. PubMed
  • Zeng H, Zhao D, Mukhopadhyay D. KDR stimulates endothelial cell migration through heterotrimeric G protein Gq/11-mediated activation of a small GTPase RhoA. J Biol Chem 2002; 277:46791-8. PubMed
  • Zeng H, Zhao D, Mukhopadhyay D. Flt-1-mediated down-regulation of endothelial cell proliferation through pertussis toxin-sensitive G proteins, beta gamma subunits, small GTPase CDC42, and partly by Rac-1. J Biol Chem 2001; 277:4003-9. PubMed
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