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Research
Interests of Wallace L. McKeehan, Ph.D. -- Molecular and
cell biology of signal transduction
Our laboratory studies how the chemical signals (polypeptide growth factors
and cytokines) in the local tissue environment control growth and specialization
of different cell types of the prostate, the liver, the vascular system,
and neural tissue. These signals determine the normal development and
function of the tissues while aberrations result in tissue dysfunctions
and diseases, such as cancer, stroke, atherosclerosis, liver and neural
disease. These signaling systems-- which are composed of a signal polypeptide
from one cell type and a reception system on another -- are the basis
for communication among cells in tissues, but also they serve as sensors
of signals like hormones and nutrients that come from outside tissues.
The cellular reception system for many signal polypeptides consists of
a transmembrane protein whose external domain interacts with signal polypeptides
and an intracellular domain which is a protein kinase enzyme which activates
metabolic pathways that control cell growth, function, and gene expression.
The
Fibroblast Growth Factor (FGF) and Transforming Growth Factor
(TGF) Beta families of intrinsic tissue regulators are at
the heart of homeostasis within adult tissues and in embryogenesis.
The FGF family is particularly interesting because it is
intimately interwoven with the peri-cellular matrix through
heparan sulfate proteoglycans which are an integral part
of the signaling system. The system senses changes in the
local environment and transmits them to the interior cells
for a response.
Our
laboratory seeks to understand the molecular mechanisms of
assembly of components of the FGF and TGF beta signaling
systems, their role in homeostasis of prostate, liver and
the cardiovascular systems and their dysfunction that results
in disease. Technologies employed in the laboratory include
recombinant DNA technologies, protein chemistry, expression
of recombinant proteins in bacteria, yeast, insect cells
and mammalian cells, primary cell culture and tissue reconstitution,
monoclonal antibodies and hybridomas and mouse transgenics.
Dr.
McKeehan's laboratory also studies the mechanism of action
of potential tumor suppressor RASSF1 through a novel complex
(LRPPRC) that integrates the microtubular cytoskeleton and
mitochondria with chromosome remodeling, genetic stability
and apoptosis. The laboratory also studies the mechanism
of action of active components in foods and edible plants
that impinge on signal transduction pathways, genetic stability
and tumor suppression and have potential value in prevention
or therapeutic intervention of disease particularly cancer.
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Representative
Publications
Yu,
C., F. Wang, M. Kan, C. Jin, R.B. Jones, M. Weinstein, C.
Deng, and W.L. McKeehan (2000) Elevated cholesterol metabolism
and bile acid synthesis in mice lacking membrane tyrosine
kinase receptor FGFR4. J. Biol. Chem. 275: 15482-15489.
Jones,
R.B., F. Wang, Y. Luo, C. Yu, C. Jin, T. Suzuki, M. Kan and
W. L. McKeehan. (2001) The nonsense-mediated decay pathway
and mutually exclusive expression of alternatively spliced
FGFR2IIIb and IIIc mRNAs. J. Biol. Chem. 276: 4158-4167.
Ye,
S., Y. Luo, W. Lu, R.B. Jones, R.J. Linhardt, I. Capila,
T. Toida, M. Kan, H. Pelletier and W.L. McKeehan (2001) Structural
basis for interaction of FGF-1, FGF-2 and FGF-7 with different
heparan sulfate motifs. Biochemistry 40: 14429-14439.
Yu,
C., F. Wang, C. Jin, X. Wu, W. Chan and W.L. McKeehan (2002)
Increased carbon tetrachloride-induced liver injury and fibrosis
in FGFR4-deficient mice. Am. J. Pathol. 161: 2003-2010.
Liu,
L., A. Vo, G. Liu and W.L. McKeehan (2002) Novel complex
integrating mitochondria and the microtubular cytoskeleton
with chromosome remodeling and tumor suppressor RASSF1 deduced
by in silico homology analysis, interaction cloning in yeast
and colocalization in cultured cells. In Vitro Cell. Devel.
Biol. Animal 38:582-594.
Complete
On-line Library of Medicine Publications with Abstracts |
