Postdoctoral Position Available

Timothy Kowalik, Ph.D.

Academic Role: Associate Professor

Faculty Appointment(s) In:
   Molecular Genetics and Microbiology

Other Affiliation(s):
   Center for AIDS Research
   Interdisciplinary Graduate Program
   Program in Immunology and Virology

Cell activation and DNA viruses

Research 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.

Recent Publications

Rogoff, H.A., Pickering, M.T., Frame, F.M., Sanchez, Y., Jones, S., and Kowalik, T.F. 2004. Apoptosis associated with deregulated E2F activity is dependent on E2F1 and Atm/Nbs1/Chk2. Mol. Cell. Biol., 24, 2968-2977.  Pubmed Article
Journal Article


Castillo, J.P., Frame, F.M., Rogoff, H.A., Pickering, M.T., and Kowalik, T.F. 2005. HCMV IE1-72 activates ATM and a p53/p21-mediated growth arrest response. J. Virol. 79, 11467-11475. Pubmed Article   Journal Article

Pickering M.T. and Kowalik, T.F. 2006. Rb inactivation leads to E2F1-mediated DNA double strand break accumulation. Oncogene, 25, 746-755. Pubmed Article  Journal Article


Frame, F.M., Rogoff, H.A., Pickering, M.T., Cress, W.D. and Kowalik, T.F. 2006. E2F1 induces Mre11 foci formation and a cell cycle checkpoint response in human fibroblasts. Oncogene, 25, 3258-3266.  Pubmed Article  Journal Article

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.

Laboratory Staff

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.

Office: S5-216
Phone: 508-856-6035
E-mail: Timothy.Kowalik@umassmed.edu
Keywords: Cancer Biology, Virology, Gene Expression

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Postdoctoral Position Available 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.