tumor cell biology program - Sylvester Comprehensive Cancer Center

HIGHLIGHTS/DISCOVERIES
• The attachment of centrosomes to intermediate
filaments is a novel observation.
Although the implications of
the mechanism of detachment during
mitosis are still to be assessed, it may
be relevant for cancer therapy.
Fulvia Verde, Ph.D.
Assistant Professor of Biochemistry
and Molecular Biology
DESCRIPTION OF RESEARCH
Dr. Verde’s research goal is to understand
the molecular basis of cell
morphogenesis in eukaryotic cells and its
coordination to cell proliferation. To this
end, her laboratory has investigated the
function of Orb6, a conserved protein
kinase that is required for maintenance
of cell polarity and regulation of the cell
cycle. Her research team has identified
two proteins that physically interact with
Orb6 and established their role in the
control of Orb6 function. One of these
proteins, Skb1, is conserved in human
cells and regulates Orb6 activity. The
other, that we named Bot1, has an important
role in localizing Orb6 to the cell
surface through its interaction with components
of the microtubule cytoskeleton.
They also have identified a potential substrate
of Orb6 kinase.
Furthermore, Dr. Verde has been
working with Tea1, a microtubule-associated
protein that functions as a marker
for cell polarity, and shows similarity to
human ERM (Ezrin, Radixin and
Moesin) proteins: they have identified
several proteins that interact with Tea1
by 2-hybrid screening. One of these proteins
has been recently shown to be essential
for spatial organization of
microtubule dynamics (Brunner and
Nurse, Cell 102, Sept1, 2000). These
findings are important because little is
known about the mechanism of microtubule-dependent
cell morphogenesis.
PUBLICATIONS
Verde, F. Cell polarity: A tale of two
Ts. Current Biology 11:R600, 2001.
Bao, S, Qyang, Y, Yang, P, Kim, H,
Du, H, Bartholomeusz, G, Henkel, J,
Pimental, R, Verde, F and Marcus, S. The
highly conserved protein methyltransferase,
Skb1, is a mediator of hyper-osmotic
stress response in the fission yeast
Schizosaccharomyces pombe. Journal of
Biological Chemistry 276:14549, 2001.
HIGHLIGHTS/DISCOVERIES
• Dr. Verde’s findings show that Bot1
may function as a molecular bridge between
Tea1, a microtubule-associated
protein required for the establishment
of cell polarity and Orb6, a conserved
protein kinase related to mammalian
Rho-kinase and Myotonic Dystrophy
kinase. These findings offer insight into
the hierarchy of events that lead to polarized
cell growth.
Keith A. Webster, Ph.D.
Associate Professor of Molecular
and Cellular Pharmacology
DESCRIPTION OF RESEARCH
Development of Gene Therapy for
the Treatment of Peripheral Arterial
Occlusive Disease, Myocardial
Ischemia, and Solid Hypoxic Tumors
Dr. Webster’s research examines the development
of gene therapy for the treatment
of peripheral arterial occlusive
disease, myocardial ischemia, and solid
hypoxic tumors. The goal of this work is
to create gene therapy delivery systems
that will allow treatment of patients suffering
from ischemia-related diseases and
solid tumors. Dr. Webster’s team has identified
the essential components of this
system and tested them in cultured cells
and intact animals using plasmid and
viral vectors. This technology is protected
by two patents—one issued, one pending.
Through examination of the pathways
of myocardial cell damage in response
to ischemia-reperfusion (I/R), Dr.
Webster has identified some of the early
signals that mediate the stress response
in cardiac myocytes during ischemia and
after reperfusion. These include release
of free radicals from mitochondria, early
activation of neutral sphingomyelinase
and ceramide production, activation of
c-Jun N-terminal kinase, p38 kinase, and
finally cell death by apoptosis or survival.
Recent work indicates that JNK activation
protects against apoptosis. Ongoing
work is deciphering the functions of the
signals, how they relate to cell death and
how they can prevent the cell death safely
using gene therapy. (See InteGene link
on the Molecular Cardiology website.)
Analyses of Gene Regulation by
Hypoxia and Ischemia in Muscle:
Glycolytic Enzyme, Endothelin-1
(ET-1), and Metallothionine Genes
These experiments have shown that a
major response of both skeletal and cardiac
muscles to hypoxia involves the coordinate
inductions of glycolytic enzyme
mRNAs. Since there are 11 glycolytic
enzyme genes and they have observed
transcript inductions of up to ten-fold
in some instances in cardiac cells over two
to three days, this response constitutes a
major switching of the muscle transcriptional
apparatus and suggests a significant
physiological adaptation. Dr.
Webster’s current and proposed studies
are focusing on the mechanism and coordination
of this response. Similarly the
ET-1 gene is over-expressed in hypoxic
and ischemic myocardial tissue, and because
ET-1 is a very powerful vasoconstrictor
its over-expression can increase
the damage caused by ischemia. They are
interested in the molecular pathway for
the regulation of ET-1 by hypoxia, which
involves the factors HIF-1, Sp1, and Sp3
and a series of accessory factors.
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UM/Sylvester Comprehensive Cancer Center Scientific Report 2002