Hi
Fasika Aklilu of McGill University, Montreal will be giving a seminar on
Thursday July 23rd in the 8th floor conference room in building 38A. The
title and abstract of her talk are below. Dr. Aklilu is a GenBank postdoc
candidate and if you are interested in speaking with her, please let me know.
David Landsman
301-435-5981

Title:
Expression of Parathyroid Hormone Related Protein (PTHRP) in Malignancy
associated Hypercalcemia

Abstract:
        Malignancy associated hypercalcemia (MH) is a secondary neoplastic
syndrome which occurs in a significant portion of cancer patients and PTHRP
has been identified as the major pathogenic factor for this disease.  In
normal physiology, PTHRP is widely expressed and has been shown to have a
broad spectrum of functions including a role in modulating cell growth and
differentiation.  In MH, PTHRP is produced in large quantities by the
cancer cells and secreted into the circulation, where it acts on bone to
stimulate bone resorption and calcium release, and on the kidneys to
increase calcium reabsorption.  The outcome of these actions is the
development of hypercalcemia, which can lead to death.
        In addition to its role in calcium homeostasis, PTHRP exerts a
proliferative effect on tumor cells.  In order to define the role of PTHRP
in malignancy, great emphasis has been given towards understand the
underlying mechanisms of its overproduction  and on its effect on tumor
growth.

A.  Molecular mechanisms of PTHRP  regulation in Malignancy
        PTHRP production is stimulated by serum, growth factors and by
oncogenes associated with the tyrosine kinase pathway.  In earlier studies,
we used wildtype and functionally impaired mutant forms of tpr-met
oncogene, and chemical inhibitors of  phosphatidylinositol (PI)-3 kinase
and ras, to demonstrate that tpr-met stimulates PTHRP through a ras
dependent pathway (Aklilu et al., Am. J. Physiol. 271:E277-83, 1996).
        As a follow up to these studies, we directly investigated the role
of ras oncogene in MH.  In this study, we employed a well characterized rat
model of MH to evaluate the effect of interfering with ras using a specific
ras processing inhibitor, B-1086, on PTHRP production in vitro and on
development of hypercalcemia in vivo.  We demonstrated that inhibiting ras
is an effective way to suppress PTHRP production and to prevent the
development of hypercalcemia.  (Aklilu et al., Cancer Research. 57(2 pt 1):
4517-22, 1997).
        Having established the role of ras in the regulation of PTHRP, we
have undertaken a study to identify downstream effectors of ras which may
mediate this effect.  The best characterized of these is the mitogen
activated protein kinase (MAPK) pathway composed of Raf, MEK, and ERK.  We
demonstrate that activation of this pathway is necessary for PTHRP gene
induction.

B. The intracellular mechanisms of PTHRP action on cell growth
        The actions of PTHRP are mediated through a G-protein coupled
receptor.  Previously, proliferative signaling had been associated with
growth factor receptors that posses an intrinsic protein tyrosine kinase
activity and the mechanisms through which G-protein coupled receptors
regulate cell proliferation is poorly understood.  Binding of PTHRP to its
receptor activates at two known signal transduction systems: a Gq -mediated
increase in intracellular inositol triphosphate and calcium levels, and
activation of protein kinase C (PKC), and a Gs-mediated activation of
cAMP-dependent protein kinase A (PKA).  Little is known about the
intracellular events that connect these pathways to the nucleus and to the
proliferative effects of PTHRP.
        Using the rat hypercalcemic leydig tumor cell system where we have
previously demonstrated the growth promoting effects of PTHRP, we show that
PTHRP stimulates the extracellular signal-regulated protein kinase (ERK)
and Jun N-terminal kinase (JNK) signalling cascades.  ERK and JNK are
members of the mitogen activated protein kinase (MAPK) family and are well
established for their role in cell proliferation.  The results from these
studies identify mediators which connect signaling by the PTHRP receptor to
the MAPK pathway, and elucidate the mechanism whereby it exerts its effect
on cellular growth.
        Understanding the molecular events that lead to overproduction of
PTHRP in malignancy, and further insight into the intracellular signaling
molecules that mediate its growth promoting effects can provide novel
therapeutic targets for better management of MH.