The overall direction of the Molecular Mechanisms of Tumor Promotion Section is to understand the mechanisms underlying the initial events in tumor promotion. Particular emphasis is being directed to the factors responsible for heterogeneity in the patterns of response. Protein kinase C is the receptor for the phorbol esters, the best studied class of tumor promoters in the mouse skin model. The mechanisms of protein kinase C activators which fail to induce phorbol ester-like responses are being characterized at the cellular and whole animal levels. The patterns of response are being correlated with the selectivity of the agents for protein kinase C isozymes. Although all tumor promoting phorbol esters are inflammatory, the converse is not true. We have found that resiniferatoxin, an ultra-inflammatory phorbol ester, acts through a unique mechanism as an analog of capsaicin, the pungent constituent of hot peppers. We have characterized the biological activity of resiniferatoxin and demonstrated the existence of resiniferatoxin receptors. Using resiniferatoxin, we can dissect components of the inflammatory response of mice to the phorbol esters. Current efforts are directed at purification of the resiniferatoxin receptors, analysis of receptor subclasses, and identification of their postulated endogenous ligand.
