Bonnie
J. Warn-Cramer, Ph.D. Assistant
Professor (Researcher), Cancer Center of Hawaii; University of Hawaii
M.A.
San Diego State University;
Ph.D. (Chemistry) University of California at San Diego
Our studies
have focused on the regulation of the connexin43 (Cx43) gap
junction protein by phosphorylation induced by growth factors
and mitogenic agents, such as the epidermal growth factor
(EGF) and lysophosphatidic acid (LPA) and by transforming
oncogenes, such as v-Src. The connexins are thought to function
as tumor suppressor proteins in the regulation of cell growth.
It is postulated that this function is mediated by the exchange
of growth regulatory signals between adjacent cells through
connexin-containing gap junctional channels. Some phosphorylation
on Cx43 is required for the proper assembly of gap junctions.
However, increased serine phosphorylation induced by EGF or
LPA or tyrosine phosphorylation induced by v-Src has been
associated with disruption of intercellular communication.
Our studies have centered on identifying the specific molecular
sites of phosphorylation, the intracellular signaling pathways
that induce phosphorylation on Cx43, and the functional effects
of phosphorylation at a specific site in the protein on the
regulation of the channel function. These studies are aimed
at increasing our understanding of how the disruption of gap
junctional communication is associated with the disregulation
of cell growth in tumor cells. For example, ovarian tumor
cells secrete LPA and LPA increases the growth rates of the
cells, the resistance of the cells to chemotherapeutic drugs,
and the production of LPA itself by the tumor cells. The effects
of LPA on Cx43 are not completely clear and we are examining
the molecular pathways and phosphorylation events that disrupt
gap junctional communication following the exposure of cells
to LPA. We are also proposing to examine proteins that have
been shown to interact with Cx43 in a yeast two-hybrid system
in order to characterize the interactions of these proteins
with Cx43 and how they may be involved in the regulation of
Cx43 function.
Selected
Publications
Warn-Cramer,
B.J., Lampe, P.D., Kurata, W.E., Kanemitsu, M.Y., Loo, L.W.M.,
Eckhart, W., and Lau, A.F. (1996) Characterization of the
mitogen-activated protein kinase phosphorylation sites on the
connexin-43 gap junction protein. Journal of Biological Chemistry,
271:3779-3786.
Martyn,
K.D., Kurata, W.E., Warn-Cramer, B.J., Burt, J., TenBroek, E.,
and Lau, A.F. (1997) Immortalized connexin43 knockout cells
display a subset of biological properties associated with the
transformed phenotype. Cell Growth and Differentiation, 8, 1015-1027.
Lampe,
P.D., Kurata, W.E., Warn-Cramer, B.J., and Lau, A.F. (1998)
Formation of a distinct connexin43 phosphoisoform in mitotic
cells is dependent upon p34cdc2 kinase. Journal of Cell Science,
111, 833-841.
Warn-Cramer,
B.J., Cottrell, G.T., Burt, J.M., and Lau, A.F. (1998) Regulation
of connexin43 gap junctional intercellular communication by
mitogen-activated protein kinase. Journal of Biological Chemistry,
273, 9188-9196.
Warn-Cramer,
B.J., Kurata, W.E., and Lau, A.F. (2000) Biochemical analysis
of connexin phosphorylation. In Methods in Molecular Biology,
Bruzzone R and Giaume C, Eds, Chapter 24, Humana Press, Totowa,
NJ, pp. 431-446.
Lau,
A.F., Warn-Cramer, B.J, and Lin, R. (2000) Regulation of
connexin43 by tyrosine protein kinases. In Current Topics in
Membranes, Perrachia C., Ed., Vol.49, Academic Press, San Diego,
CA, pp.315-341.
