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Hong Zhang PhD

TitleAssociate Professor
InstitutionUMass Chan Medical School
AddressUMass Chan Medical School
55 Lake Avenue North
Worcester MA 01655
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    Other Positions
    InstitutionT.H. Chan School of Medicine

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentInterdisciplinary Graduate Program

    InstitutionMorningside Graduate School of Biomedical Sciences

    InstitutionMorningside Graduate School of Biomedical Sciences
    DepartmentPostbaccalaureate Research Education Program

    Collapse Biography 
    Collapse education and training
    Fudan University, Shanghai, 31, ChinaBSBiology
    Michigan State University, East Lansing, MI, United StatesPHDGenetics

    Collapse Overview 
    Collapse overview

    Cell and Developmental Biology Department

    Zhang Lab Website


    Hong Zhang received his B.S. from Fudan University in China and Ph.D. from Michigan State University. He received postdoctoral training at Stanford University School of Medicine, and joined the faculty in the Department of Cell Biology at University of Massachusetts Medical School in 2006. He is a New Scholar in Aging of the Ellison Medical Foundation.

    Genetic Regulation of Senescence in Cancer, Aging and Stem Cell Self-renewal; Molecular Targeting of E3 Ligases in Transcriptional Regulation

    My lab is interested in the genetic regulation of senescence in cancer, aging and stem cell self-renewal. Senescence, a process by which cells enter an irreversible growth arrest state, is activated by many stimuli, including telomere attrition, aberrant oncogenic signaling, DNA damage or oxidative stress. Increasing evidence suggests that senescence acts as a tumor suppression mechanism. By limiting cell proliferation, senescence impedes the accumulation of multiple mutations that are necessary for tumorigenesis. Furthermore, senescence activated by aberrant oncogenic activation, DNA damage or oxidative stress provides a failsafe mechanism that prevents proliferation of cells at risk of neoplastic transformation. However, cell proliferation is critical for renewal, repair and regeneration to maintain normal tissue homeostasis and functions. By limiting cell proliferation and consequently depleting the renewal capacity of stem or progenitor cells, senescence is thought to contribute to the aging process. Therefore, senescence is regarded as an antagonistic pleiotropy in cancer and aging: benefits organisms for survival and fitness early in life by acting as a tumor suppressor, but has a detrimental effect on the survival and fitness of organisms later in life by contributing to aging. This view of senescence regulation in aging and cancer provides a plausible explanation for the logic of aging and is consistent with the evolutionary theory of aging. The specific projects that are being investigated in the lab are listed below.

    Genetic pathways of senescence: Using forward genetic screen as well as reverse genetics, we are interested in elucidating the genetic pathways that govern senescence. Towards this goal, we have identified a number of genes that control senescence activation and will continue to search for additional senescence regulators. We are interested in understanding the underlying molecular mechanisms of senescence regulation by these genes.

    Senescence regulation in oncogenesis: To investigate the function of senescence in tumorigenesis, we are generating novel mouse models, in which senescence response is modulated. Our strategy of modulating senescence response in vivo is to manipulate the expression of key senescence regulators identified in our genetic screen studies. One such regulator is Smurf2, an E3 ligase. We have generated a Smurf2-deficient mouse model as well as conditional Smurf2 transgenic mouse models. Our ongoing studies indicate that Smurf2-deficient mouse embryonic fibroblasts exhibit delayed senescence entry and enhanced potential to become immortalized in culture. Furthermore, Smurf2-deficient mice spontaneously develop tumors at higher frequency as compared to wild-type mice, suggesting that Smurf2 is a tumor suppressor. Studies using Smurf2-deficient mice are complemented by our studies using the conditional Smurf2 transgenics. Using these "senescence" mouse models, combined with different tumorigenesis models (for instance, p53 knockout, B cell lymphoma, skin cancer, colon cancer and liver cancer models), we hope to gain a better understanding of the regulation and contribution of senescence in tumor development.

    Senescence in aging and stem cell self-renewal: The mouse models we have generated to modulate senescence response in vivo are also used in our studies of senescence regulation in aging, with an emphasis on adult stem cells. For instance, declining hematopoiesis is a well characterized aspect of immune senescence. In aged mice, the self-renewal capacity of long-term hematopoietic stem cells (LT-HSC) diminishes. Our ongoing studies have found that LT-HSC population, which give rise to all lineages of blood cells, increases in Smurf2-deficient mice, suggesting a beneficial effect of Smurf2 deficiency. Studies are designed to investigate whether the function and self-renewal capacity of Smurf2-deficient LT-HSC are enhanced, whether such enhanced function of HSCs provides benefit to mice during aging, and whether senescence plays a role in HSC self-renewal and regulation during aging.

    As aging is accompanied by increased susceptibility to all major chronic diseases, including cardiovascular disease, cancer, Alzheimer's disease, diabetes, arthritis and osteoporosis, we are taking a systematic approach to analyze the impact of senescence on stem cell self-renewal in various tissues/organs, including bone marrow, bone, skin, pancreas, brain and kidney. Understanding the underlying mechanisms of age-associated decline in the renewal capacity of stem cells will help us gain better understanding of aging.

    Molecular targeting of E3 ligase in transcriptional regulation: Smurf2 belongs to the Nedd4 family of E3 ligase. In mammals, all nine members share similar structure features: N-terminal C2 domain, C-terminal catalytic HECT domain and 2-4 WW domains in the middle to mediate protein-protein interaction with substrates. WW domain is known to interact with PPXY motif in substrates, yet how such interaction determines substrate specificity is not clear. PPXY motif is found in many transcription factors, including those involved in TGF-? signaling, Wnt signaling, and polycomb complex. Using an unbiased genetic screen, we are interested in identifying E3 ligases that are responsible for the ubiquitination of these important transcriptional factors, the consequence of dysregulation of such ubiquitination in diseases including cancer, and the specificity of substrate recognition by different members of the Nedd4 family of E3 ligases.


    Zhang Figure 1

    Figure 1. Microarray analysis of senescence induced by Smurf2 vs. replicative senescence

    Zhang Figure 2

    Figure 2. Smurf2-deficient mice exhibit increased spontaneous tumorigenesis

    Zhang Figure 3

    Figure 3. Smurf2-deficient mice have increased hematopoietic stem cell population (Lin-c-kit++Sca1+ CD150+CD135-)

    Zhang Figure 4

    Figure 4. Smurf2 ubiquitinates transcriptional repressor Id1


    Collapse Rotation Projects

    Rotation Opportunities

    1. Germinal center response in lymphomagenesis
    2. Smurf2's role in autoimmunity and its link with lymphoma development
    3. Hematopoietic stem cell quiescence, senescence and aging
    4. Genetic screen of senescence regulators using genome-wide shRNA-mediated gene silencing
    5. Characterization of substrate specificity of HECT family E3 ligases 

    Collapse Post Docs

    Postdoctoral Position Available

    A postdoctoral fellow position is available in the Zhang laboratory. Areas of study include the molecular mechanisms of senescence and its functions in cancer and aging. Both cell culture and mouse models are used. A Ph.D. in molecular and cellular biology, genetics, or a related field is required. Prior experience in cell culture and mouse genetics is desirable. Please send curriculum vitae to Dr. Zhang (hong.zhang@umassmed.edu).

    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    Newest   |   Oldest   |   Most Cited   |   Most Discussed   |   Timeline   |   Field Summary   |   Plain Text
    PMC Citations indicate the number of times the publication was cited by articles in PubMed Central, and the Altmetric score represents citations in news articles and social media. (Note that publications are often cited in additional ways that are not shown here.) Fields are based on how the National Library of Medicine (NLM) classifies the publication's journal and might not represent the specific topic of the publication. Translation tags are based on the publication type and the MeSH terms NLM assigns to the publication. Some publications (especially newer ones and publications not in PubMed) might not yet be assigned Field or Translation tags.) Click a Field or Translation tag to filter the publications.
    1. Trabucco SE, Gerstein RM, Zhang H. YY1 Regulates the Germinal Center Reaction by Inhibiting Apoptosis. J Immunol. 2016 09 01; 197(5):1699-707. PMID: 27448584.
      Citations: 11     Fields:    Translation:AnimalsCells
    2. Trabucco SE, Zhang H. Finding Shangri-La: Limiting the Impact of Senescence on Aging. Cell Stem Cell. 2016 Mar 03; 18(3):305-6. PMID: 26942849.
      Citations: 2     Fields:    
    3. Huang H, Veien ES, Zhang H, Ayers DC, Song J. Skeletal Characterization of Smurf2-Deficient Mice and In Vitro Analysis of Smurf2-Deficient Chondrocytes. PLoS One. 2016; 11(1):e0148088. PMID: 26815610.
      Citations: 12     Fields:    Translation:AnimalsCells
    4. Mori M, Mahoney JE, Stupnikov MR, Paez-Cortez JR, Szymaniak AD, Varelas X, Herrick DB, Schwob J, Zhang H, Cardoso WV. Notch3-Jagged signaling controls the pool of undifferentiated airway progenitors. Development. 2015 Jan 15; 142(2):258-67. PMID: 25564622.
      Citations: 74     Fields:    Translation:HumansAnimalsCells
    5. Trabucco SE, Gerstein RM, Evens AM, Bradner JE, Shultz LD, Greiner DL, Zhang H. Inhibition of bromodomain proteins for the treatment of human diffuse large B-cell lymphoma. Clin Cancer Res. 2015 Jan 01; 21(1):113-22. PMID: 25009295.
      Citations: 61     Fields:    Translation:HumansAnimalsCells
    6. Obri A, Makinistoglu MP, Zhang H, Karsenty G. HDAC4 integrates PTH and sympathetic signaling in osteoblasts. J Cell Biol. 2014 Jun 23; 205(6):771-80. PMID: 24934156.
      Citations: 30     Fields:    Translation:AnimalsCells
    7. Ramkumar C, Kong Y, Trabucco SE, Gerstein RM, Zhang H. Smurf2 regulates hematopoietic stem cell self-renewal and aging. Aging Cell. 2014 Jun; 13(3):478-86. PMID: 24494704.
      Citations: 7     Fields:    Translation:AnimalsCells
    8. Swanson EC, Manning B, Zhang H, Lawrence JB. Higher-order unfolding of satellite heterochromatin is a consistent and early event in cell senescence. J Cell Biol. 2013 Dec 23; 203(6):929-42. PMID: 24344186.
      Citations: 125     Fields:    Translation:HumansAnimalsCells
    9. Cui H, Kong Y, Xu M, Zhang H. Notch3 functions as a tumor suppressor by controlling cellular senescence. Cancer Res. 2013 Jun 01; 73(11):3451-9. PMID: 23610446.
      Citations: 52     Fields:    Translation:HumansCells
    10. Ramkumar C, Cui H, Kong Y, Jones SN, Gerstein RM, Zhang H. Smurf2 suppresses B-cell proliferation and lymphomagenesis by mediating ubiquitination and degradation of YY1. Nat Commun. 2013; 4:2598. PMID: 24121673.
      Citations: 37     Fields:    Translation:HumansAnimalsCells
    11. Ramkumar C, Kong Y, Cui H, Hao S, Jones SN, Gerstein RM, Zhang H. Smurf2 regulates the senescence response and suppresses tumorigenesis in mice. Cancer Res. 2012 Jun 01; 72(11):2714-9. PMID: 22552287.
      Citations: 25     Fields:    Translation:Animals
    12. Kong Y, Cui H, Zhang H. Smurf2-mediated ubiquitination and degradation of Id1 regulates p16 expression during senescence. Aging Cell. 2011 Dec; 10(6):1038-46. PMID: 21933340.
      Citations: 36     Fields:    Translation:HumansCells
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