 |
Professor of Biochemistry & Molecular Biology
PO Box 980614
Richmond, VA 23298-0614
Email: alarner@vcu.edu
Telephone: 804-828-2903
Education
- M.D., 1981, University of Virginia
- Ph.D., 1982, University of Virginia
Post-Doc
1982-1985, Rockefeller University
Website: www.star-man.org/dad/
Research
The focus of my research for the past 15 years has been to understand the signals that are activated by interferons
(IFNs) binding to their cell surface receptors that result in the biological actions of these cytokines. Initially
we focused our attention on the cascades that lead to the expression of immediate early genes by incubation of
cultured cells with either IFNa/ß (type 1 interferons) or IFNγ (type 2 interferon). The findings from my lab along
with several others resulted in the delineation of the Jak/Stat Pathway as a key cascade that regulates the
expression of early response genes by not only interferons but also a variety of other cytokines. Interferon
activation of the Jak family of tyrosine kinases leads to the tyrosine phosphorylation of both interferon receptor
subunits and Stat transcription factors that translocate to the nucleus where they bind enhancers in responsive
genes to stimulate their transcription. It is clear from several studies including ones published from my lab that
IFN activation of the Jak/Stat pathway is necessary, but not sufficient for the biological actions of these
cytokines. In addition to activation of the Jak/Stat pathway, we have shown that interferons also regulate other
well-defined signaling cascades including ERK1 and PI-3 kinase. During the past 5 years my research has focused on
two areas of interferon biology. One topic concerns changes in the signaling events that control interferon
stimulated early response genes in cells that have been previously desensitized to this cytokine. The information
from the latter studies has implications in how one chronically administers these and possibly other cytokines for
therapy of a variety of diseases such as multiple sclerosis. The other area of interest concerns the regulation of
immune responses and cell growth through activation of the Stat3 transcription factor. The current model dictates
that binding of cytokines such as interleukin-6 and interleukin-10 to their cell surface receptors induces tyrosine
and serine phosphorylation of Stat3 resulting in its nuclear accumulation and binding to a GAS enhancer in the
promoters of Stat3-responsive genes. Recent experiments in the lab provide the first evidence for the presence of
Stat3 in mitochondria of cultured cells as well as primary tissues including liver and heart. In Stat3 -/- primary
pro B cells cellular ATP levels and the activities of complexes I and II of the electron transport chain (ETC) are
decreased by 50 - 90%. Stat3 expressed in Stat3 -/- cells, which is targeted to the mitochondria restores the
functions of complexes I and II. In mice that do not express Stat3 in the heart there are also selective defects in
the activities of these components of the electron transport chain. These data indicate that mitochondrial-
localized Stat3 contributes novel functions which may orchestrate responses to cellular stress and innate immunity
through modulating the activity of the ETC and the production of ATP. They also suggest that the subcellular
localization of a protein can drastically alter its
Publications
|
|
 |
 |
1101 E Marshall St | PO Box 980614 | Richmond, VA 23298 | ph 804.828.9762 | fax 804.828.1473
Site Update July 20, 2008, Responsible Unit - Department of Biochemistry & Molecular Biology, biochemgrad@mail.vcu.edu
Virginia Commonwealth University,
VCU School of Medicine
|
