Research Interests Biology of SV40 and related tumor viruses. Simian virus 40 (SV40) and its close relatives in the Polyomavirus group cause tumors in test animals and induce neoplastic transformation in cultured cells. Some of these viruses cause pathologies including cancer or neurodegenerative disease, in their natural hosts. The Pipas laboratory seeks to understand the strategies SV40 uses for infection, and how viral infection leads to disease. The laboratory is focused on a single virus-encoded protein, the 708 amino acid large T antigen (LT). LT is a multifunctional protein that orchestrates virtually every aspect of SV40 infection (DNA replication, transcription, virion assembly) and is necessary and often sufficient for tumorigenesis. At least part of LT's ability to induce tumors stems from its ability to bind specific cellular tumor suppressor proteins such as p53 or pRb (retinoblastoma protein). Recently the Pipas group collaborated with Dr. Jeff Brodsky's laboratory here in the Department to show that LT is a member of the DnaJ family of molecular chaperones, and that LT chaperone activity is required for tumorigenesis. The Pipas and Brodsky labs continue their collaboration and are undertaking a series of biochemical, genetic, and cell culture approaches aimed at elucidating the mechanism by which LT blocks tumor suppressor action. Intestinal growth control and tumorigenesis in transgenic and gene knock-out mice. In order to understand how alterations in the activities of oncogenes and tumor suppressors leads to tumorigenesis, the Pipas lab is focusing on the mouse intestine as a model system. The villi of the intestine are composed of growth-arrested, terminally-differentiated cells, mostly enterocytes. These cells function for a few days before they are replaced by new cells that migrate up the villus from the intestinal crypts. The crypts contain stem cells that are constantly dividing in the cell-cycle. Because the stem and differentiated cell populations are in physically distinct compartments, they can be separated and isolated for protein activity or gene expression studies. Current work in the Pipas lab focuses on using transgenic and gene knock-out mice to understand: (1) the role of the interactions between the retinoblastoma (Rb) family of tumor suppressors and the E2F family of transcription factors in regulating intestinal development and growth control; and (2) the cell signaling pathway alterations that drive each step in tumor progression. Molecular genetics of human cancer. The Pipas laboratory continues a longstanding collaboration with Dr. Arnold Meisler (Oncology) and Dr. Mona Melhem (Pathology) aimed at dissecting the events that lead to human colorectal cancer. These investigators are taking several approaches aimed at identifying the key genetic changes that drive tumor progression, especially metastasis. Towards this end they have established and maintained a tumor bank and patient registry so that genetic changes can be correlated with tumor pathology and patient outcome. One approach is directed towards identifying changes in gene structure or expression that occur during tumorigenesis. Currently they are utilizing DNA chip technologies to examine broad changes in gene expression in benign and malignant tumors. Another approach examines the role of cell-cell contact and cell-extracellular matrix interactions in tumorigenesis and metastasis. The Meisler/Melhem/Pipas collaboration is in the process of taking a similar approach to investigate the molecular genetics of prostate cancer.   Selected Publications Kozuch PS, Rocha-Lima CM, Dragovich T, Hochster H, O'Neil BH, Atiq OT, Pipas JM, Ryan DP, Lenz HJ. Bortezomib with or without irinotecan in relapsed or refractory colorectal cancer: results from a randomized phase II study. J Clin Oncol. 2008 May 10;26(14):2320-6. Zhao X, Madden-Fuentes RJ, Lou BX, Pipas JM, Gerhardt J, Rigell CJ, Fanning E. Ataxia telangiectasia-mutated damage-signaling kinase- and proteasome-dependent destruction of Mre11-Rad50-Nbs1 subunits in Simian virus 40-infected primate cells. J Virol. 2008 Jun;82(11):5316-28. Greer SE, Pipas JM, Sutton JE, Zaki BI, Tsapakos M, Colacchio TA, Gibson JJ, Wiener DC, Ripple GH, Barth RJ Jr. Effect of neoadjuvant therapy on local recurrence after resection of pancreatic adenocarcinoma. J Am Coll Surg. 2008 Mar;206(3):451-7. Wright CM, Chovatiya RJ, Jameson NE, Turner DM, Zhu G, Werner S, Huryn DM, Pipas JM, Day BW, Wipf P, Brodsky JL. Pyrimidinone-peptoid hybrid molecules with distinct effects on molecular chaperone function and cell proliferation. Bioorg Med Chem. 2007 Dec 14. Sáenz-Robles MT, Markovics JA, Chong JL, Opavsky R, Whitehead RH, Leone G, Pipas JM. Intestinal hyperplasia induced by simian virus 40 large tumor antigen requires E2F2.J Virol. 2007 Dec;81(23):13191-9. Complete Publication Listing   Grant Support NIH: Expression of simian virus 40 T antigens in intestine. Role: Principal Investigator NIH: Action of the SV40 chaperone machine on tumor suppressors. Role: Principal Investigator NIH: SV40 T antigen: Role in virus growth and transformation. Role: Principal Investigator   Other Links Department of Biological Sciences University of Pittsburgh

James M Pipas, Ph.D. Office:  559B Crawford Hall Lab:578 - 559 Crawford Hall Phone:(412) 624-4691 Lab (412) 624-4322 Fax: (412) 624-4759 pipas@pitt.edu   Academic Affiliations Department of Biological Sciences   Education 1971 B.S. Chemistry University of Southern Mississippi Hattiesburg, MS 1975 Ph.D. Molecular Biophysics Florida State University Tallahassee, FL Postdoctoral studies with John Wilson at Baylor College and with Dan Nathans at the Johns Hopkins School of Medicine   Lab Personnel Faculty: Dr. Mayte Saenz-Robles Dr. Ping An Post-Doctoral: Dr. Abhilasha Rathi Staff: Paul Cantalupo Chikdu Shivalila Graduate Students: Nicole Seneca Undergraduate Researchers: Natalie Allen Nick Giacobbi Vladimir Lamm