The overall direction of the Molecular Mechanisms of Tumor Promotion Section is to understand the regulation of the signalling pathways downstream from the lipophilic second messenger diacylglycerol, to elucidate the basis for heterogeneity of response to different ligands which function through this pathway, and to exploit this understanding for developing novel ligands with unique behaviour that function through this pathway. A complementary direction is to understand the regulation and structure activity relations for the vanilloid receptor. The vanilloid receptor is a downstream target of the diacylglycerol signalling pathway, shares partial homology in its ligands to this pathway, and shares with the diacylglycerol signalling pathway an important role in inflammation. Both directions impact both our understanding of biological regulation and the potential development of therapeutic agents. Protein kinase C, the best studied downstream target for diacylglycerol, represents the classic system for tumor promotion and is a therapeutic target for cancer chemotherapy. The vanilloid receptor represents a promising therapeutic target for cancer pain, among other indications, and thus represents an important direction in palliative care for cancer patients. Exploiting strong collaborations with groups in computational chemistry and synthetic chemistry, we continue to improve our understanding of the structural basis for ligand - protein kinase C interactions. In a major advance, we have demonstrated that the C1 domains of the so-called atypical PKCs zeta and iota retain the basic structure involved in ligand binding. This advance causes a major revision of our understanding of C1 domain structures. Building on this understanding, we and the Marquez group have begun to design ligands selective for this class of targets, which are thought to play a critical role in colon cancer. In other studies, we have developed a strategy for the rational design of additional points of interaction between ligands and protein kinase C. Bryostatin is in clinical trials as a protein kinase C activator with a unique pattern of induced response. We find that it suppresses phosphorylation of protein kinase C delta on tyrosine, a critical regulatory step, and causes much more transient activation of the AP-1 signaling pathway than do the phorbol esters. PEP005 is another protein kinase C activator in clinical trials for actinic keratosis and non-melanotic skin cancer. Our studies reveal that it differs from the typical phorbol ester in its modulation of the NFkB response pathway. RasGRP3 is an activator of the Ras pathway directly stimulated by diacylglycerol and phorbol esters. We find that it is expressed at elevated levels in a range of solid tumors and contributes to their phenotype. In the development of therapeutics targeted to TRPV1, a major problem is designing sufficient specificity of action. We find that its ligand recognition depends on its state of regulatory control. This finding implies that ligands can be designed that will be specific for the vanilloid receptor in a specific regulatory environment, such as at a site of inflammation. Current studies are assessing the roles of individual regulatory elements in the pattern of ligand recognition.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Intramural Research (Z01)
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National Cancer Institute Division of Basic Sciences
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Cooke, Mariana; Zhou, Xiaoling; Casado-Medrano, Victoria et al. (2018) Characterization of AJH-836, a diacylglycerol-lactone with selectivity for novel PKC isozymes. J Biol Chem 293:8330-8341
Das, Joydip; Kedei, Noemi; Kelsey, Jessica S et al. (2018) Critical Role of Trp-588 of Presynaptic Munc13-1 for Ligand Binding and Membrane Translocation. Biochemistry 57:732-741
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Elhalem, Eleonora; Donadío, Lucía Gandolfi; Zhou, Xiaoling et al. (2017) Exploring the influence of indololactone structure on selectivity for binding to the C1 domains of PKC?, PKC?, and RasGRP. Bioorg Med Chem 25:2971-2980
Czikora, Agnes; Kedei, Noemi; Kalish, Heather et al. (2017) Importance of the REM (Ras exchange) domain for membrane interactions by RasGRP3. Biochim Biophys Acta Biomembr 1859:2350-2360
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Feng, Zhiwei; Pearce, Larry V; Zhang, Yu et al. (2016) Multi-Functional Diarylurea Small Molecule Inhibitors of TRPV1 with Therapeutic Potential for Neuroinflammation. AAPS J 18:898-913
Zhang, Feng; Hanson, Sonya M; Jara-Oseguera, Andres et al. (2016) Engineering vanilloid-sensitivity into the rat TRPV2 channel. Elife 5:
Petersen, Mark E; Kedei, Noemi; Lewin, Nancy E et al. (2016) Replacement of the Bryostatin A- and B-Pyran Rings With Phenyl Rings Leads to Loss of High Affinity Binding With PKC. Tetrahedron Lett 57:4749-4753

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