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    Timothy F Kowalik PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentMicrobiology and Physiological Systems
    AddressUniversity of Massachusetts Medical School
    55 Lake Avenue North
    Worcester MA 01655
    Phone508-856-6035
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentCancer Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentImmunology and Virology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMolecular Genetics and Microbiology

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentCenter for AIDS Research

        Overview 
        Narrative

        Academic Background

        Timothy Kowalik received his B.S. degree in Biology and Mathematics from Belmont Abbey College in 1982. He received his M.S. (1986) and his Ph.D. (1989) in Molecular Biology and Virology from Utah State University. Dr. Kowalik did postdoctoral research on virus-cell interactions from 1990-1993 at the Lineberger Cancer Center of the University of North Carolina. From 1993-1996, he continued his postdoctoral studies in the Department of Genetics at Duke University Medical Center where he analyzed the relationship between the cell cycle and apoptosis. During his postdoctoral training, Dr. Kowalik was a Fellow of the Damon Runyon-Walter Winchell Cancer Research Fund and a Leukemia Society of America Special Fellow. In 1996, Dr. Kowalik joined the Department of Molecular Genetics and Microbiology at the University of Massachusetts Medical School where he is an associate professor.

        Cell activation and DNA viruses

        Photo: Timothy 
F. KowalikResearch in my laboratory centers around the regulation of cellular proliferation control especially from the perspective of an infecting virus. To maximize yields, small DNA tumor viruses encode activities which trick infected cells into proliferative states. This is often achieved by subverting normal homeostatic controls resulting in infected cells progressing into S phase. For small DNA viruses, this entails inactivating the Rb and p53 tumor suppressors. Rb inactivation results in the activation of the E2F transcription factor family which induces expression of genes involved in nucleotide and DNA biosynthesis. Genetic and biochemical studies have demonstrated that Rb inactivation and induction of E2F transcriptional activity normally occur in late G1 and are central to the progression of cells through G1 and into S phase.

        Using recombinant adenovirus technology, we are presently examining the paradoxical relationship between growth activation by E2F1 overexpression and the resultant p53-dependent apoptotic cell death. We are also studying the consequences of Rb and p53 targeting by large DNA tumor viruses including members of the herpesvirus family.



        Rotation Projects

        Rotation Projects

        1. Identify the region on E2F1 responsible for p53-mediated apoptosis. We know that a transcriptionally functional E2F1 is required for apoptosis signaling. We also know that E2F2 does not induce apoptosis in our system. Therefore, domains on E2F1 and E2F2 will be swapped to determine which E2F1 domain is responsible for apoptosis signaling.


        2. Role of nuclear kinases in E2F1 mediated apoptosis. Our recent efforts have revealed that E2F1 expression leads to the phosphorylation of p53 and this modification correlates with apoptosis. There are several candidate kinases that need to be analyzed for their contribution to p53 phosphorylation. A dominant negative approach will be used in this project to identify which kinase(s) contribute to the E2F1 signal to p53.


        3. Role of CMV IE proteins in proliferation. We have found that both IE1 and IE2 target different Rb family members. IE2 binds to Rb and IE1 interacts with p107. We now know that IE2 is a strong inducer of S phase but IE1 can only significantly modulate proliferation in cells lacking p53. We are interested in knowing why p53 can prevent IE1 from inducing S phase.


        4. Mechanism of p53 accumulation by CMV. It has recently been shown that CMV infection results in an accumulation of p53. We have recently found that IE1 expression also leads to p53 accumulation. We wish to determine the steps leading to p53 accumulation and the consequences of this event.


        Post Docs

        Postdoctoral positions are available to study the relationship(s) between the Rb/E2F proliferation pathway and p53-dependent apoptosis. Areas of investigation include understanding why E2F1 is unique among the E2F family in its strong apoptosis signaling ability and determining the pathways that lead from E2F1 activation to cell death. Fellows will be associated with a highly motivated and interactive group of researchers studying aspects of cell cycle, apoptosis signaling and cancer using cell culture, virology and animal models.

        If interested, please contact:

          Timothy Kowalik
          Department of Molecular Genetics and Microbiology
          University of Massachusetts Medical School
          55 Lake Avenue North
          Worcester, MA 01655

        The University of Massachusetts Medical School is an Affirmative Action / Equal Opportunity Employer.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Bhattacharjee B, Renzette N, Kowalik TF. Genetic analysis of cytomegalovirus in malignant gliomas. J Virol. 2012 Jun; 86(12):6815-24.
          View in: PubMed
        2. E X, Stadler BM, Debatis M, Wang S, Lu S, Kowalik TF. RNA interference-mediated targeting of human cytomegalovirus immediate-early or early gene products inhibits viral replication with differential effects on cellular functions. J Virol. 2012 May; 86(10):5660-73.
          View in: PubMed
        3. Renzette N, Bhattacharjee B, Jensen JD, Gibson L, Kowalik TF. Extensive genome-wide variability of human cytomegalovirus in congenitally infected infants. PLoS Pathog. 2011 May; 7(5):e1001344.
          View in: PubMed
        4. E X, Pickering MT, Debatis M, Castillo J, Lagadinos A, Wang S, Lu S, Kowalik TF. An E2F1-Mediated DNA Damage Response Contributes to the Replication of Human Cytomegalovirus. PLoS Pathog. 2011 May; 7(5):e1001342.
          View in: PubMed
        5. E X, Hwang S, Oh S, Lee JS, Jeong JH, Gwack Y, Kowalik TF, Sun R, Jung JU, Liang C. Viral Bcl-2-mediated evasion of autophagy aids chronic infection of gammaherpesvirus 68. PLoS Pathog. 2009 Oct; 5(10):e1000609.
          View in: PubMed
        6. Ghosh JC, Dohi T, Raskett CM, Kowalik TF, Altieri DC. Activated checkpoint kinase 2 provides a survival signal for tumor cells. Cancer Res. 2006 Dec 15; 66(24):11576-9.
          View in: PubMed
        7. Liang X, Pickering MT, Cho NH, Chang H, Volkert MR, Kowalik TF, Jung JU. Deregulation of DNA damage signal transduction by herpesvirus latency-associated M2. J Virol. 2006 Jun; 80(12):5862-74.
          View in: PubMed
        8. Shin YC, Nakamura H, Liang X, Feng P, Chang H, Kowalik TF, Jung JU. Inhibition of the ATM/p53 signal transduction pathway by Kaposi's sarcoma-associated herpesvirus interferon regulatory factor 1. J Virol. 2006 Mar; 80(5):2257-66.
          View in: PubMed
        9. Bradley SP, Rastellini C, da Costa MA, Kowalik TF, Bloomenthal AB, Brown M, Cicalese L, Basadonna GP, Uknis ME. Gene silencing in the endocrine pancreas mediated by short-interfering RNA. Pancreas. 2005 Nov; 31(4):373-9.
          View in: PubMed
        10. Castillo JP, Frame FM, Rogoff HA, Pickering MT, Yurochko AD, Kowalik TF. Human cytomegalovirus IE1-72 activates ataxia telangiectasia mutated kinase and a p53/p21-mediated growth arrest response. J Virol. 2005 Sep; 79(17):11467-75.
          View in: PubMed
        11. Rogoff HA, Kowalik TF. Life, death and E2F: linking proliferation control and DNA damage signaling via E2F1. Cell Cycle. 2004 Jul; 3(7):845-6.
          View in: PubMed
        12. Rogoff HA, Pickering MT, Frame FM, Debatis ME, Sanchez Y, Jones S, Kowalik TF. Apoptosis associated with deregulated E2F activity is dependent on E2F1 and Atm/Nbs1/Chk2. Mol Cell Biol. 2004 Apr; 24(7):2968-77.
          View in: PubMed
        13. Castillo JP, Kowalik TF. HCMV infection: modulating the cell cycle and cell death. Int Rev Immunol. 2004 Jan-Apr; 23(1-2):113-39.
          View in: PubMed
        14. Heinen CD, Goss KH, Cornelius JR, Babcock GF, Knudsen ES, Kowalik T, Groden J. The APC tumor suppressor controls entry into S-phase through its ability to regulate the cyclin D/RB pathway. Gastroenterology. 2002 Sep; 123(3):751-63.
          View in: PubMed
        15. Rogoff HA, Pickering MT, Debatis ME, Jones S, Kowalik TF. E2F1 induces phosphorylation of p53 that is coincident with p53 accumulation and apoptosis. Mol Cell Biol. 2002 Aug; 22(15):5308-18.
          View in: PubMed
        16. Kowalik TF. Smad about E2F. TGFbeta repressionof c-Myc via a Smad3/E2F/p107 complex. Mol Cell. 2002 Jul; 10(1):7-8.
          View in: PubMed
        17. Angus SP, Fribourg AF, Markey MP, Williams SL, Horn HF, DeGregori J, Kowalik TF, Fukasawa K, Knudsen ES. Active RB elicits late G1/S inhibition. Exp Cell Res. 2002 Jun 10; 276(2):201-13.
          View in: PubMed
        18. Castillo JP, Kowalik TF. Human cytomegalovirus immediate early proteins and cell growth control. Gene. 2002 May 15; 290(1-2):19-34.
          View in: PubMed
        19. Strobeck MW, Reisman DN, Gunawardena RW, Betz BL, Angus SP, Knudsen KE, Kowalik TF, Weissman BE, Knudsen ES. Compensation of BRG-1 function by Brm: insight into the role of the core SWI-SNF subunits in retinoblastoma tumor suppressor signaling. J Biol Chem. 2002 Feb 15; 277(7):4782-9.
          View in: PubMed
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