Patricia S. Lorenzo, PhD
	Associate Professor (Researcher), Cancer Research Center of Hawai‘i; Graduate Faculty, Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawai‘i PhD (Pharmacology), University of Buenos Aires, Argentina; MS (Biochemistry), University of Buenos Aires, Argentina; MS (Pharmacy), University of Buenos Aires, Argentina plorenzo@crch.hawaii.edu

Publication list via PubMed

Research interest
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 (click here to see diagram). 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.

 

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Selected Publications

Diez FR, Garrido AA, Sharma A, Luke CT, Stone JC, Dower NA, Cline JM and Lorenzo PS. RasGRP1-transgenic mice develop cutaneous squamous cell carcinomas in response to skin wounding: potential role of granulocyte colony-stimulating factor. Am J Pathol. 2009 Jun 4. [Epub ahead of print].

Luke CT*, Oki-Idouchi CE*, Cline J.M and Lorenzo PS. RasGRP1 overexpression in the epidermis of transgenic mice contributes to tumor progression during mouse skin carcinogenesis. Cancer Res. 67: 10190-10197, 2007. *share first authorship.

Oki-Idouchi CE and Lorenzo PS. Transgenic overexpression of RasGRP1 in mouse epidermis results in spontaneous tumors of the skin. Cancer Res. 67:276-280, 2007.

Okamura SM, Oki-Idouchi CE and Lorenzo PS. The exchange factor and diacylglycerol receptor RasGRP3 interacts with dynein light chain 1 through its C-terminal domain. J. Biol. Chem. 281: 36132-36139, 2006.

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, 2006.

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.

Lorenzo PS and Dennis, PA. Modulating Protein kinase C (PKC) to increase the efficacy of chemotherapy: stepping into darkness. Drug Resist. Updat. 6: 329-339, 2003.

Active Grants

P.S. Lorenzo, Principal Investigator
R01 CA096841
"Regulation of Tumor Promotion by RasGRP1"
September 2, 2003-May 31, 2010

P.S. Lorenzo, Co-Principal Investigator Project IV Cancer Biology-Molecular Targeting of Metastatasis
Congressional Special Interest (CSI), DOD-MRMC
"Collaborative Cancer Research between Tripler Army Medical Center (TAMC) and the Cancer Research Center of the University of Hawaii (CRCH)"
March 1, 2006-February 28, 2010

P.S. Lorenzo, Principal Investigator
Hawaii Community Foundation - Medical Research Grant
"RasGRP1 in human non-melanoma skin cancer"
November 2, 2007-October 31, 2009

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