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

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 viruses 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 result in viral pathogenesis and 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, metabolism.

Description of Research

Dr. Alwine studies how DNA viral infections alter cellular pathways, metabolism and biocynthesis, and deal with the consequences, the induction of 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.

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.

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.

Buchkovich, N.J., Maguire, T.G. Yu, Y., Paton, A.W., Paton, J.C. and J.C. Alwine (2008). HCMV specifically controls the levels of the endoplasmic reticulum chaperone BiP/GRP78 which is required for virion assembly. J. Virol. 82:31-39.

Buchkovich, N.J. Y. Yu, C.A. Zampieri and J.C. Alwine. (2008). The TORrid affairs of viruses: The effects of mammalian DNA viruses on the PI3K-Akt-mTOR signaling pathway. Nature Reviews Microbiology. 6:265-275.

Search PubMed for more articles

Lab

Rotation Projects

Rotation projects in the following areas are available:

1. Examining the means by which human cytomegalovirus and simian virus 40 circumvent the deleterious effects of cellular stress responses caused by hypoxia, reactive oxygen species, the unfolded proteisn response (UPR) etc.
2. Studies of the involvement of immunoglobulin binding protein (BiP) in HCMV virion assembly and egress. Our studies of the UPR have indicated that BiP, the cellular protein which has major control of the UPR, is also essential for viral assembly and egress.
3. Studies of HCMV’s effects of cellular metabolism. HCMV dramatically alters the cellular utilization of glucose. Using ¹³C-NMR we are determining metabolic flux during infection.

Lab personnel

Yongjun Yu, Ph.D. Senior Research Investigator
Carisa Zampieri, Ph.D. Postdoctoral Fellow
Jermey Chambers, Ph.D. Postdoctoral Fellow
Nick Buchkovich, CAMB/CGC Student
Tobi Maguire, Lab Manager