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
negative (ER-) breast cancers. Her laboratory has
found that oncogenic receptor tyrosine kinase
and cSrc activation may not only activate mitogenic
signaling leading to aggressive proliferation, it
may also lead to loss of detectable ER protein in
ER- breast cancers. One-third of newly diagnosed
breast cancers are ER- and have a poor prognosis.
Investigation of mechanisms underlying loss of
ER expression showed that all of 70 primary ERbreast
cancers expressed ER mRNA. Src or
proteasome inhibition increased ER levels and
Src transfection stimulated both ligand-activated
ER transcriptional activity and ER proteolysis.
Cotransfection of Her2 and Src reduced ER levels
further. ER- primary breast cancers and cell lines
showed increased Src activity compared to ER+
cancers and cell lines, and the ER protein half-life
was reduced in ER- breast cancer lines. These
data support a model in which Her2 and cSrc
cooperate with liganded ER to promote both ER
dependent transcription and transcription linked
ER proteolysis.
SELECTED PUBLICATIONS
2002
Donovan, JC, Rothenstein, JM, and Slingerland,
JM. Non-malignant and tumor-derived cells differ
in their requirement for p27Kip1 in transforming
growth factor-beta-mediated G1 arrest.
Journal of Biological Chemistry 277:41686-92,
2002.
Liang, J, Zubovitz, J, Petrocelli, T, Kotchetkov, R,
Connor, MK, Han, K, Lee, JH, Ciarallo, S,
Catzavelos, C, Beniston, R, Franssen, E, and
Slingerland, JM . PKB/Akt phosphorylates p27,
impairs nuclear import of p27 and opposes p27-
mediated G1 arrest. Nature Medicine 8:1153-60,
2002.
Ciarallo, S, Subramaniam, V, Hung, W, Lee, JH,
Kotchetkov, R, Sandhu, C, Milic, A, and
Slingerland, JM . Altered p27(Kip1) phosphorylation,
localization, and function in human epithelial
cells resistant to transforming growth
factor beta-mediated G(1) arrest. Molecular and
Cellular Biology 22:2993-3002, 2002.
2003
Connor, MK, Kotchetkov, R, Cariou, S, Resch,
A, Lupetti, R, Beniston, RG, Melchior, F,
Hengst, L, and Slingerland, JM . CRM1/Ranmediated
nuclear export of p27(Kip1) involves a
nuclear export signal and links p27 export and
proteolysis. Molecular Biology of the Cell
14:201-13, 2003.
Liang, J and Slingerland, JM . Multiple roles of
the PI3K/PKB (Akt) pathway in cell cycle progression.
Cell Cycle 2:339-45, 2003.
FULVIA VERDE, PH.D.
Assistant Professor of Molecular and
Cellular Pharmacology
DESCRIPTION OF RESEARCH
Control of Cell Morphogenesis
Dr. Verde’s research seeks to understand the
molecular basis of cell morphogenesis in eukaryotic
cells and its coordination to cell proliferation.
To this end, Dr. Verde and her colleagues
have investigated the function of Orb6, a conserved
protein kinase that is required for maintenance
of cell polarity and regulation of the cell
cycle. They have identified six proteins that
physically interact with Orb6 and established
their role in the control of Orb6 function. Five of
these proteins are conserved in human cells.
These factors are involved in Orb6 activity regulation,
are implicated in the control of Orb6 intracellular
localization, or function as substrate
effectors of Orb6 kinase in the control of cell
morphology and the cell cycle.
Furthermore, Dr. Verde’s laboratory 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 organi-
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 95