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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
Education
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.
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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
last updated 8/2007
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