Patricia
Lorenzo, Ph.D.
Associate
Professor (Researcher), Cancer Research Center of Hawaii;
Graduate Faculty, Department of Cell and Molecular Biology, John
A. Burns School of Medicine, University of Hawaii
MS
Biochemistry, University of Buenos Aires, Argentina;
MS Pharmacy, University of Buenos Aires, Argentina;
Ph.D. Pharmacology, University of Buenos Aires, Argentina
Our
laboratory is interested in understanding the signaling
pathways involving the second messenger diacylglycerol
and their participation in carcinogenesis, particularly
during tumor promotion. Carcinogenesis is believed to involve
three stages: initiation of an irreversible genetic lesion,
promotion of growth of the initiated cells, and progression
of the initial tumor to malignancy. Since tumor promotion
accounts for most of the latent period in carcinogenesis
and is a reversible process, the various components of
this stage can be potential targets for the development
of mechanism-based anticancer and chemopreventive drugs.
As
tools to analyze diacylglycerol signaling pathways in carcinogenesis,
we have been using a group of natural products that mimic
some of the actions of this second messenger in the cell.
One of the natural products is the phorbol ester 12-O-tetradecanoylphorbol-13-acetate
(TPA), a structural analog of diacylglycerol with potent
tumor promoting activity in mouse skin. For many years,
phorbol esters and diacylglycerol were thought to act only
through activation and modulation of the Protein Kinase
C (PKC) family. However, new families of diacylglycerol
receptors have been discovered, including PKD, chimaerins,
Munc 13, RasGRP, and DGK. Therefore,
members of these families could also mediate some of the
phorbol esters/diacylglycerol effects that have been so
far solely attributed to PKC activation, like tumor promotion.
Our
current research effort is directed to the study of RasGRP
in tumor promotion, using the multistage carcinogenesis
of the mouse skin as our main model system. We have recently
documented the expression of one of the members of the
RasGRP family -RasGRP1- in epidermal keratinocytes, which
are the target cells in tumor promotion in skin. Furthermore,
we have demonstrated that in keratinocytes TPA induces
Ras activation in a PKC-independent manner and induces
the translocation and down-regulation of RasGRP1, suggesting
that RasGRP1 is an additional diacylglycerol/phorbol ester
receptor in skin. Ongoing studies are directed towards
the investigation of RasGRP1 signaling in keratinocytes
and its participation in tumor promotion induced by TPA
utilizing both, knockout and transgenic models.
Selected
Publications
Tuthill
MC, Oki CE and Lorenzo PS. Differential effects of bryostatin
1 and 12-O-tetradecanoyl-phorbol-13-acetate on the regulation
and activation of RasGRP1 in mouse epidermal keratinocytes.
Mol. Cancer Ther. 5: 602-610, 1006.
Rambaratsignh
R, Stone JC, Blumberg PM and Lorenzo PS. RasGRP1 is a novel,
non-PKC signaling pathway in epidermal keratinocytes. J. Biol.
Chem. 278: 52792-52801, 2003.
Rong
SB, Enyedy IJ, Qiao L, Zhao L, Ma D, Pearce LL, Lorenzo PS,
Stone JC, Blumberg PM, Wang S and Kozikowski AP. Structural
basis of RasGRP binding to high-affinity PKC ligands. J. Med.
Chem. 45: 853-860, 2002.
Lorenzo
PS, Kung JW, Bottorff DA, Garfield SH, Stone JC and Blumberg
PM. Phorbol esters modulate the Ras exchange factor RasGRP3.
Cancer Res. 61: 943-949, 2001.
Shao
L, Lewin NE, Lorenzo PS, Hu Z, Enyedy IJ, Garfield SH, Stone
JC, Marner FJ, Blumberg PM and Wang S. Iridals are a novel
class of ligands for phorbol ester receptors with modest selectivity
for the RasGRP receptor subfamily. J. Med. Chem. 44: 3872-3880,
2001.
Lorenzo
PS, Beheshti M, Pettit GR, Stone JC and Blumberg PM. The guanine
nucleotide exchange factor RasGRP is a high affinity target
for diacylglycerol and phorbol esters. Mol. Pharmacol. 57:
840-846, 2000.
