SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

T U M O R C E L L B I O L O G Y P R O G R A M
CATHERINE F. WELSH, M.D.
Associate Professor of Medicine
DESCRIPTION OF RESEARCH
Dr. Welsh studies the cell cycle progression
through the G1 phase and its regulation by
growth factor receptors and adhesion to the extracellular
matrix. Her laboratory is particularly interested
in how these signaling pathways
contribute to breast cancer tumorigenesis and
progression. Signals from the plasma membrane
emanating from receptor tyrosine kinases as well
as integrins are each required for G1 progression.
Cell spreading and cytoskeletal integrity as a consequence
of integrin engagement also are necessary.
Their laboratory studies involve the role of
Rho family GTPases, a subset of the Ras superfamily,
in the regulation of adhesion-dependent
cell cycle progression. These proteins have been
shown to play a role in integrin- and growth factor-mediated
signaling, and they are potent mediators
of cytoskeletal architecture during cell
spreading. They are therefore situated to play a
key role in the regulation of adhesion-dependent
cell cycle progression. Recent research has revealed
that Rho GTPases become deregulated in
breast cancer and may contribute to tumorigenesis.
Dr. Welsh’s laboratory is currently investigating
the contribution of Rho GTPases to
abnormalities in cell cycle proteins that typify
poor prognosis breast cancer.
HIGHLIGHTS/DISCOVERIES
• Rho family GTPases are in fact required for key
adhesion-dependent G1 events, including
cyclin D1 expression, Rb phosphorylation, and
cyclin A expression. In addition, they participate
in the activation of the mitogen-activated
kinase, ERK1/2, a key upstream regulator of
cyclin D1 expression. Furthermore, Rho proteins
appear to be involved in determining the
timing of cyclin D1 expression within G1
phase.
• Hyperactivation of Rho proteins in a subset of
breast cancers underlies abnormalities in cell
cycle regulators that typify poor prognosis
breast cancer. In addition, inactivation of Rho
GTPases normalizes these regulatory molecules
and restores a more orderly progression through
the cell cycle, even in aggressively growing
breast cancer cells. Pathways mediating these
actions include the MEK-ERK pathway. These
findings may have implications for more targeted
therapeutic approaches that specifically
inhibit the autonomous proliferation of breast
cancer cells.
RUDOLF K. WERNER, PH.D.
Professor of Biochemistry and
Molecular Biology
DESCRIPTION OF RESEARCH
Dr. Werner’s research focuses on the regulation
of connexin43 expression. He and his colleagues
had discovered that the 5’-UTR of
connexin43 mRNA contains a very active internal
ribosome entry site (IRES) element that appears
to be regulated by estrogen. His laboratory
continues to investigate this regulation in the
myometrium where connexin43 is produced at
parturition in response to estrogen. Dr. Werner’s
research also has demonstrated that in several
other tissues, such as heart and smooth muscle,
connexin43 pre-mRNA is alternatively spliced
producing mRNA with different 5’-UTRs but
identical coding regions. This finding suggests
that the expression of connexin43 is regulated at
the translational level in different tissues.
Dr. Werner and his colleagues discovered
alternatively spliced 5’-UTR-coding exons in five
other connexins. Again, the splicing seems to be
tissue-specific. They currently are investigating
whether some of these novel exons contain IRES
elements.
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UM/Sylvester Comprehensive Cancer Center Scientific Report 2004