Research


Extracellular Matrix and Metalloproteinases in Development and Diseases

Dr. Zhongjun Zhou

Zhongjun Zhou, PhD

Associate Professor, Department of Biochemistry

BSc (Xiamen Univ.); PhD (Karolinska Inst, Sweden; CAMS & PUMC, China)

Contact
Email: zhongjun@hkucc.hku.hk
Tel: (852) 2819 9542
Office: L3-71, Laboratory Block, 21 Sassoon Road, Hong Kong
Awards and Distinctions
  • State Science and Technology Award (2nd Class) 2011, State Council, CHINA
  • International Society of Matrix Biology Nominated Speaker 2007 Cains, Australia
  • Outstanding Research Output Award 2006, Faculty of Medicine, University of Hong Kong
  • Distinguished Oversea Young Chinese Scientist Award 2005, Natural Science Foundation of China
  • Young Investigator Award 2000, International Society of Fibrinolysis and Proteolysis, Japan
  • Swedish Cancer Foundation Fellow 1996-1997, Swedish Cancer Fond, Sweden
Editorship
Academic Editor of PLoS One

Postgraduate Research Projects Available:

  • Genomic Instability in Premature aging and Cancer
  • MT1-MMP in growth factor signaling, angiogenesis and tumorigenesis
  • Stem cell self-renewal in cancer and aging
  • Regulation of DNA-damage checkpoint response and repair by lamin A/C

Research Description:

We are interested in understanding the in vivo functions of metalloproteinases. In collaboration with groups in Karolinska Institute and University of Ovid, Spain, we have generated several knockout mice and are currently analyzing functions of these genes during the development and in various physiological and pathological conditions.

Zmpste24 is a metalloproteinase on ER responsible for the maturation of prelamin A, a nuclear scaffold protein that is also suggested to be involved in DNA replication and RNA splicing. A specific mutation in LMNA gene exposes a cryptic splicing site and results in 50 aa deletion in prelamin A protein, leading to Hutchinson Gilford Progerial. Mouse lacking Zmpste24 results in unprocessed prelamin A and recapitulates many of the progeroid phenotypes found in HGPS. We have shown that laminopathy-based premature aging is a consequence of genomic instability caused by defective DNA-damage checkpoint response/repair due to compromised recruitment of these proteins to DNA damage sites. We are now investigating how such mutation in LMNA affect epigenetic control and chromatin structure, compromising DNA repair machinery. Uncovering the underlying mechanism not only helps to understand aging process but also provides novel strategy to fight against cancer.

Expt results

Laminopathy-based premature aging is a result of genomic instability caused by defective recruitment of DNA-damage checkpoint/repair proteins 10 minutes (left panel) and 12 hours (right panel) after DNA damage

MMPs are responsible for the turnover of extracellular matrix, therefore playing central roles in cellular differentiation, proliferation and migration. Amongst many MMPs, membrane-type metalloproteinase (Mmp14, MT1-MMP) is the first one to give severe phenotypes in null mice, indicating the importance of this gene for life. MT1-MMP deficiency results in a variety of developmental abnormalities including dwarfism, craniofacial dismorphysism, defective angiogenesis and early death. The mechanisms behind and the contribution of MT1-MMP to angiogenesis (blood vessel branching) are now under investigation. Our particular interest is on how MT1-MMP regulates fibroblast growth factor signaling.

Stem cell self-renewal is an important aspect in aging and cancer. We are now investigating how unprocessed prelamin A affects stem cells self-renewal, aging and tumorigenesis.

Team Members:

  • Baohua LIU, PhD student; BSc, Peking University
  • Kui Ming CHAN, PhD student; BSc, University of Hong Kong
  • Jiang LI, PhD student; MPhil, Inst of Cell Biology and Biochemistry, CAS
  • Le ZANG, MPhil student; BSc, Peking University
  • Pauline CHAU, MPhil student; BSc, University of Hong Kong
  • Guoxiang JIN, PhD student; BSc, Zhejiang University

New Staff:

  • Zimei Wang, Research Associate; MBBS, Hebei Med. Univ.; PhD, Peking Union Medical College
  • Grace C T Kong, Postdoc fellow; BSc, Polytech Univ Hong Kong, PhD, University of Hong Kong
  • Juergen Scharner; BSc. Austria; MPhil student
  • Xuewei Wu; PhD student; MPhil, Fujian Normal University
  • Huifang Liu; PhD student, BSc, Peking University

Former Members:

  • Vaidehi Krishnan, Postdoc fellow; PhD, Bombay University, India; Postodoc,IMCB, Singapore
  • Karen Ka Ki Woo, Research Assistant; BSc, University of Toronto, Canada
Members of Zhou's lab

Publications, Achievements, and Grants:

Selected Publications (*correspondence):

  • K Chan, H Wong, G Jin, B Liu, R Cao, Y Cao, K Lehti, K Tryggvason and Z Zhou*. MT1-MMP Inactivates ADAM9 to Regulate FGFR2 Signaling in Calvarial Osteogenesis. Dev Cell 2012 May (in press)
  • G Jin, F Zhang, K M Chan, H L Wong, B Liu, K Cheah, X Liu, C Mauch, D Liu, Z Zhou*. MT1-MMP cleaves Dll1 to negatively regulate Notch signaling to maintain normal B cell development. EMBO J  2011, 30, 2281 - 2293
  •  V Krishnan, M Z Chow, Z Wang, L Zhang, B Liu, X Liu and Z Zhou*. Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice. Proc Natl Aca Sci USA  2011,108 (30);12325-12330
  • Kar B, Liu B, Zhou Z, Lam Y W.  Quantitative nucleolar proteomics reveals nuclear re-organization during stress-induced senescence in mouse fibroblast.  BMC Cell Biology 2011, 12:33
  • JR Delaney, G L Sutphin, B Dulken, S Sim, J R Kim, B Robison, J Schleit, C J Murakami, D Carr, E H. An, E Choi, A Chou,M Fletcher, M Jelic, B Liu, D Lockshon, R M. Moller, D N. Park, Q Peng, Z J Peng, K M. Pham, M Sage, A Solanky, K K. Steffen, M Tsuchiya, S Tsuchiyama, S Johnson, C Raabe, Y Suh, Z Zhou, X Liu, B K. Kennedy, and Matt Kaeberlein. Sir2 deletion prevents life span extension in 32 long-lived Sir2 deletion prevents life span extension in 32 long-lived mutants mutants. Aging Cell  2011, 10(6):1089-1091
  • Sugiyama N, Varjosalo M, Meller P, Lohi J, Chan KM, Zhou Z, Alitalo K, Taipale J, Keski-Oja J, Lehti K.  FGF receptor-4 (FGFR4) polymorphism acts as an activity switch of a membrane type 1 matrix metalloproteinase-FGFR4 complex. Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15786-91.  
  • Gawden-Bone C, Zhou Z, King E, Prescott A, Watts C, Lucocq J. Dendritic cell podosomes are protrusive and invade the extracellular matrix using metalloproteinase MMP-14. J Cell Sci. 2010;123(Pt 9):1427-37
  • She ZG, Zheng W, Wei YS, Chen HZ, Wang AB, Li HL, Liu G, Zhang R, Liu JJ, Stallcup WB, Zhou Z, Liu DP, Liang CC. Human Paraoxonase Gene Cluster Transgenic Overexpression Represses Atherogenesis and Promotes Atherosclerotic Plaque Stability in ApoE-Null Mice. Circ Res. 2009, 22;104(10):1160-8.
  • Mimura T, Han KY, Onguchi T, Chang JH, Kim TI, Kojima T, Zhou Z, Azar DT.  MT1-MMP-Mediated Cleavage of Decorin in Corneal Angiogenesis. J Vasc Res. 2009;46(6):541-50
  • Wang, Z., Zhou Z., Liu, D.P., and Huang, J.D. Double-stranded break can be repaired by single-stranded oligonucleotides via the ATM/ATR pathway in mammalian cells. Oligonucleotides, (2008), V 18(1):21-32
  • Kandert S, Kleinhenz T, Neumann S, Lu W, Jaeger VM, Munck M, Wehnert M, Müller CR, Zhou Z, Noegel AA, Dabauvalle MC and Karakesisoglou I  Nesprin-2 giant safeguards nuclear envelope architecture in LMNA S143F progeria cells. Human Molecular Genetics 2007 16(23):2944-2959
  • West MA, Prescott AR, Chan KM, Zhou Z, Rose-John S, Scheller J, Watts C.   TLR ligand-induced podosome disassembly in dendritic cells is ADAM17 dependent. J Cell Biol. 2008 Sep 8;182(5):993-1005.
  • Wang J, Hoshijima M, Lam J, Zhou Z, Jokiel A, Dalton ND, Hultenby K, Ruiz-Lozano P, Ross J Jr, Tryggvason K, Chien KR.  Cardiomyopathy associated with microcirculation dysfunction in laminin alpha 4 chain deficient mice.  J Biol Chem. 2006, 6;281(1):213-20
  • Bjorndahl M, Cao R, Nissen LJ, Clasper S, Johnson LA, Xue Y, Zhou Z, Jackson D, Hansen AJ, Cao Y. Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo. Proc Natl Acad Sci U S A. 2005, 102(43):15593-8
  • P Religa, R Cao, M Bjorndahl, Z Zhou, Z Zhu, and Y Cao. Presence of bone marrow-derived circulating progenitor endothelial cells in the newly formed lymphatic vessels. Blood 2005, 106(13), 4184-90
  • Liu B, Wang J, Chan KM, Tjia WM, Deng W, Guan X, Huang JD, Li KM, Chau PY, Chen DJ, Pei D, Pendas AM, Cadinanos J, Lopez-Otin C, Tse HF, Hutchison C, Chen J, Cao Y, Cheah KS, Tryggvason K, Zhou Z.*  Genomic instability in laminopathy-based premature aging.  Nature Medicine 2005, 11 (7), 780-785 * correspondence 
    Comment by Misteli T, Scaffidi P. In Nat Med 2005 11(7):718-9
    Genome instability in progeria: when repair gets old.
    Recommended by Faculty 1000 by two members, F1000 Factor 6.4
    Tom Misteli: This study points to a potential molecular mechanism for the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS).
    Yosef Gruenbaum: This exciting paper provides evidence that unprocessed lamin A and truncated lamin A cause aberrant DNA damage response and repair, resulting in genomic instability.
  • Varela I, Cadinanos J, Pendas AM, Gutierrez-Fernandez A, Folgueras AR, Sanchez LM, Zhou Z, Rodriguez FJ, Stewart CL, Vega JA, Tryggvason K, Freije JM, Lopez-Otin C. Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation. Nature 2005  437(7058):564-8
    Recommended by Faculty 1000 by M. Sharon Stack, F1000 Factor 6.0  an intriguing link between ageing and tumor suppression.
  • Oblander SA, Zhou Z, Galvez BG, Tryggvason K and Apte SS. Distinctive functions of membrane type 1 matrix-metalloprotease (MT1-MMP or MMP-14) in lung and submandibular gland development are independent of its role in pro-MMP-2 activation. Dev. Biol. 2005; (277), 255-269
  • Zhou Z*, Doi M, Wang J, Cao R, Liu B, Chan KM, Kortesmaa J, Sorokin L, Cao Y, Tryggvason K. Deletion in laminin a4 results in increased tumor angiogenesis and metastasis  Cancer Res.  2004; 64(12), 4059-4063 *correspondence 
    Recommended by Faculty 1000 by Lynn Matrisian, F1000 Factor 3.0
    This paper reports the surprising result that deletion of laminin-8 increases pathological angiogenesis, including tumor angiogenesis and metastasis in mice.
  • Zhou Z*, Wang J, Cao R, Morita H, Soininen R, Chan KM, Liu B, Cao Y, Tryggvason K. Impaired angiogenesis, delayed wound healing and retarded tumor growth in Perlecan heparan sulfate deficient mice.  Cancer Res.   2004; 64(14), 4699-4702 * correspondence
  • Pendás A*, Zhou Z*, Cadinanos J, Freije JM, Wang J, Hultenby K, Astudillo A, Wernerson A, Rodriguez F, Tryggvason K, Lopez-Otin C.  Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase–deficient mice.  Nature Genetics  2002; 31(1): 94-99  *Equal contribution
  • Franzke C, Tasanen K, Schäcke H, Zhou Z, Tryggvason K, Mauch C, Zigrino P, Sunnarborg S, Lee DC, Fahrenholz F, Bruckner-Tuderman L. Transmembrane Collagen XVII, an Epithelial Adhesion Protein, is Shed from the Cell Surface by ADAMs. EMBO J. 2002; 21(19):5026-35.
  • Zhou Z, Soininen R, Cao R, Baaklini GY, Rauser RW, Wang J, Cao Y, Tryggvason K.  Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I.  Proc Natl Acad Sci U S A 2000; 97(8):4052-7