Our Science – Blumberg Website

Peter M. Blumberg, Ph.D.

Laboratory of Cancer Biology and Genetics Head, Molecular Mechanisms of Tumor Promotion Section Senior Investigator Building 37, Room 4048B 37 Convent Drive MSC4255 Bethesda, MD 20892-4255 Phone:   301-496-3189 Fax:   301-496-8709 E-Mail:   blumberp@dc37a.nci.nih.gov

Biography

Dr. Blumberg received both his A.B., summa cum laude, and his Ph.D. from the Department of Biochemistry and Molecular Biology, Harvard University. He was Helen Hay Whitney fellow at the Cancer Center, Massachusetts Institute of Technology, and was assistant and associate professor of pharmacology at Harvard Medical School. Since 1981, Dr. Blumberg has been chief of the Molecular Mechanisms of Tumor Promotion Section.

Research

Mechanism of Action of Phorbol Esters and Related Derivatives

The central focus of the program of the Molecular Mechanisms of Tumor Promotion Section is to elucidate the pathways of signal transduction for the lipophilic second messenger sn-1,2-diacylglycerol, as well as for the exogenous, ultrapotent analogs, the phorbol ester tumor promoters. Protein kinase C (PKC), the major receptor for these compounds, receives particular emphasis, but attention is also directed at identifying factors responsible for differences in regulation between protein kinase C, protein kinase D, the chimaerins, and RasGRP. As part of an extensive collaborative effort with the Laboratory of Medicinal Chemistry, we seek to understand the nature and consequences of phorbol ester binding to the regulatory domain of PKC and its related receptors. An important milestone in this ongoing program is the development of synthetic ligands with nM affinities and with unique selectivity. Using a combinatorial chemical approach, for example, we have identified ligands with marked selectivity for RasGRP relative to PKC. In other work, we have shown that shown that dioxolanones, derivatives of the diacylglycerol lactones, possess a unique pattern of interaction with the receptor binding site. A second aspect of our program is to understand how the behavior of the binding domain is modified in the context of the intact receptor molecule, the membrane, and the cell. Using site-directed mutagenesis, we have identified critical residues lining the rim of the binding pocket of the atypical PKC isoforms which are responsible for its lack of ligand binding. A third aspect is to understand the role and ligand selectivity of the classes of phorbol ester receptors other than protein kinase C. Here, particular attention is being directed toward RasGRP, which we find to contribute to the transformed phenotype in multiple tumor types.

Our second general area of focus is on the mechanism of action of capsaicin. These studies developed from our finding that resiniferatoxin, a natural product structurally related to the phorbol esters, acts not on protein kinase C but rather as a unique, ultrapotent analog of capsaicin, the pungent constituent of red pepper. These studies are driven by the potential of such analogs to desensitize capsaicin-sensitive neurons, which are involved in pain transmission, and thus to represent a novel class of nonnarcotic analgesics. Using resiniferatoxin, we have been able to develop a ligand-binding assay for vanilloid receptors. As part of a collaborative effort with medicinal chemists, we seek to identify more potent, synthetic agonists, to design antagonists, and find molecules that function as partial agonists. At the biological level, we wish to understand how ligand binding and cellular assays of activity translate into whole animal response. At the mechanistic level, we seek to understand both the structural basis for ligand interaction and the regulatory processes responsible for desensitization of pain pathways.

Our collaborators include Victor Marquez, NIH; Jeewoo Lee, Seoul National University; Alan Kozikowski, University of Illinois at Chicago; Chaya Brodie, Henry Ford Hospital;; James Stone, University of Alberta; Jane Wang, University of Pittsburgh; Patricia Lorenzo, University of Hawaii; Stuart Yuspa, NIH; Attila Toth, University of Debrecen; Tamas Biro, University of Debrecen.

This page was last updated on 6/11/2008.