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Diacylglycerol Pathways in Cancer
Diacylglycerol is a second messenger produced on the hydrolysis of phosphoinositides by a specific phospholipase C (PLC), or from phosphatidylcholine by the action of phospholipase D (PLD). This second messenger triggers downstream cell signaling by activating different intracellular targets. Six different families of diacylglycerol targets have been discovered so far: Protein Kinase C (PKC), Protein Kinase D (PKD), chimaerins, MUNC 13, Diacylglycerol Kinases (DGK) and RasGRP (see below). The interaction between diacylglycerol and its receptor is mediated by the C1 domain.
Downstream activation of the diacylglycerol targets generates numerous responses, which depend on the tissue and the target activated. For example, diacylglycerol signaling has been involved in proliferative effects, apoptosis and differentiation. In certain pathological conditions, like cancer, some of these signaling pathways are compromised, either overactivated or downregulated.
Currently, the lab focuses on the study of RasGRP pathways in cancer. RasGRP is a family of guanine nucleotide exchange factors (GEF) for Ras small GTPases, and as such, its function is to catalyze the GDP-GTP exchange of Ras like proteins.
Our early studies in the lab of Dr. Peter Blumberg at NCI, demonstrated that RasGRP1 and RasGRP3 are both high affinity receptors for phorbol esters, which are ultrapotent analogs of diacylglycerol. Interestingly, the typical phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA ), is a potent tumor promoter in mouse skin. this prompted us to study whether RasGRP could mediate TPA effects in the epidermis. We found that RasGRP1 is expressed in mouse epidermal keratinocytes and mediates TPA-induced Ras activation in these cells. More recently, with the use of a transgenic mouse model for overexpression of RasGRP1 in the epidermis, we have demonstrated a role of RasGRP1 in skin carcinogenesis. Ongoing studies address the mechanisms of action of RasGRP1 during carcinogenesis (initiation-promotion-progression). The specific research projects in the lab are described below.
Specific Projects
1) RasGRP1 and mouse skin carcinogenesis Our studies are directed towards the investigation of RasGRP1 signaling in mouse keratinocytes and its participation in skin carcinogenesis utilizing both, knockout and transgenic mouse models. This project is supported by NCI.
2) RasGRP1 in human keratinocyte biology and transformation We are investigating the role of RasGRP1 in human epidermal cells, utilizing 3-D organotypic cultures (skin reconstructs). This project is supported by Hawaii Community Foundation.
3) Role of RasGRP in angiogenesis We are examining the participation of some of the RasGRP isoforms in the effect of diacylglycerol analogs in angiogenesis, using HUVEC (human umbilical vein endothelial cells) as our model. This project is supported by Department of Defense.
Natural Products Screening
In collaboration with Dr. Thomas Hemscheidt from the Department of Chemistry at University of Hawaii, we run bioassays to screen natural products from marine organisms in search of anticancer agents. The research efforts are supported in part by a grant from the National Science Foundation and the National Institute of Environmental Health Sciences to the Pacific Research Center for Marine Biomedicine. We are also collaborating with Drs. Marcus Tius (Department of Chemistry, UHawaii Manoa) and Gideon Berger (Hawaii Pacific University) in the screen for anti-angiogenic compounds. |
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Research |
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The primary research interest of the laboratory is the study of the role of diacylglycerol pathways in cancer. As part of the Natural Products & Cancer Biology Program, we also participate in the in the screening of natural products in search of novel anticancer agents. |
