Jim Alwine, Ph.D.
Professor, Dept of Cancer Biology

Microbiology, Virology and Parasitology Program

Address

314 Biomedical Rsch Bldg II/III (Office)
320-323 Biomedical Rsch Bldg II/III (Lab)
421 Curie Boulevard
Philadelphia, PA 19104-6140

Office tel.: 215 898-3256
Lab tel.: 215 898-6464
Fax: 215 573-3888
E-mail: alwine@mail.med.upenn.edu

Link(s)

Dr. Alwine at the Abramson Institute

Elizabethtown College: BS (Chemistry), 1969.

Pennsylvania State University: Ph.D. (Biological Chemistry), 1974.

Stanford University: Postdoctoral Research (Biochemistry), 1974-77.

National Cancer Institute, National Institutes of Health: Postdoctoral Research (Molecular Virology), 1977-1980.

Research Interests

The molecular mechanisms by which viral regulatory proteins adapt cellular functions in order to prepare the cell for viral replication and to circumvent the inhibitory effects of cellular stress responses induced during infection. These adaptations may increase the oncogenic potential of a cell.

Key words: Molecular Virology, cell growth, cancer, Virus-host interactions, , SV40, T antigen, HCMV, immediate early proteins, mTOR signaling, unfolded protein response.

Search PubMed for articles

Description of Research

Dr. Alwine studies how DNA viral infections deal with the consequences of inducing cellular stress responses. During infection by DNA viruses, such as human cytomegalovirus (HCMV; a herpesvirus) and simian virus 40 (SV40), cellular stress responses are triggered by the viral infection; for example, by the stress resulting from the greatly increased metabolic and synthetic rates needed for successful viral replication. Stress responses may be induced due to nutrient deprivation, hypoxia or the induction of the unfolded protein response (UPR), a form of endoplasmic reticulum stress. Stress responses are normally activated when the cell is in distress, and are designed to slow down cellular processes to allow the cell to recover. If recovery is impossible, the stress responses can lead to apoptosis. Such conditions would not favor DNA virus replication. For example, a major effect of most stress responses is the inhibition of translation, which would inhibit the synthesis of viral proteins; and apoptosis would be a severe disadvantage to the replicating DNA virus. Dr. Alwine’s work has shown that the viruses induce mechanisms which circumvent the inhibitory effects of stress responses. Examining viral effects on translational controls, he and his colleagues have shown that during SV40 and HCMV infections the activities of cellular kinases such as PI3K/Akt, mTOR, and the signaling pathways of the UPR are significantly altered for the advantage of the viral replication. This results in the maintenance of translation and other cellular metabolic processes, even under conditions where stress responses are trying to inhibit them. The goal of the work in the lab is to determine how the virus medicates these changes. We want to know the viral proteins involved and how they interact with cellular pathways. In this regard, it should be kept in mind that DNA viruses, like HCMV, do not often utilize novel, viral-specific biochemistry. Instead they induce, modify, mimic or preempt existing cellular mechanisms. In other words, the mechanisms used by viruses may mimic control mechanisms available to uninfected cells under specific conditions. Thus, while our studies highlight mechanisms of viral pathogenesis, they also elucidate pathways operative in uninfected cell.

How does this relate to Cancer? The cellular proteins affected by viral infection ( PI3K, Akt, mTOR, mTOR effectors and the signaling kinases of the UPR) are all known oncogenes. Thus their activation by viral infection can aid transformation, or increase the oncogenic potential of a cell. It is important to determine which viral proteins exert these functions, which cellular proteins are affected and the mechanisms used. These studies will give insight into viral mechanisms of transformation and will highlight cellular proteins which may contribute to oncogenesis if their control mechanisms are abrogated.

Recent Publications

Yu, Y. and J.C. Alwine (2005). Effects of Simian Virus 40 Large and Small Tumor Antigens on Mammalian Target of Rapamycin (mTOR) Signaling: Small Tumor Antigen Mediates Hypophosphorylation of eIF4E-Binding Protein 1 (4E-BP1) Late in Infection. J. Virol. 79:6882-6889.

Isler, J.A., Skalet, A.H. and J.C. Alwine (2005). Human Cytomegalovirus Infection Activates and Regulates the Unfolded Protein Response. J. Virol. 79:6890-6899.

Isler, J.A., Maguire, T.G. and J.C. Alwine (2005). Production of Infectious HCMV Virions is Inhibited by Drugs that Disrupt Calcium Homeostasis in the Endoplasmic Reticulum. J. Virol. 79:15388-15397

Kudchodkar, S.B., Yu, Y., Maguire, T.G. and J.C. Alwine (2006). Human Cytomegalovirus Infection Alters the Substrate Specificities and Rapamycin Sensitivities of Raptor- and Rictor-Containing Complexes. Proc. Natl. Acad. Sci. USA 103:14182-14187.

Kudchodkar, S.B., Del Prete, G.Q., Maguire, T.G. and J.C. Alwine (2007). AMPK-Mediated Inhibition of mTOR Kinase is Circumvented during Immediate Early Times of HCMV Infection. J. Virol. 81:3649-3651.

Lab

Rotation Projects

Rotation projects will examine the means by which the human cytomegalovirus and simian virus 40 circumvent the deleterious effects of cellular stress responses. Stress responses are induced during infection and normally would result in inhibition of cellular processes needed by the virus (e.g. translation). In circumventing these responses the viruses maintain translation and virus production but induce pathogenesis. The viral proteins which mediate these effects and the cellular proteins affected will be identified in order to determine mechanisms. Make an appointment, come by to chat.

Lab personnel:

Yongjun Yu, Ph.D. Research Associate
Carisa Zampieri, Ph.D. Postodoctoral Fellow
Nick Buchkovich, CAMB/CGC Student
Tobi Maguire, Lab Manager