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: Possible Correlation with Tumor-promoting Activity
Molecular Mechanisms of Tumor Promotion Section, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland 20892-4255 [K. B., P. S. L., P. Á., G. S. W., P. M. B.], and Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814 [Z. S.]
Protein kinase C (PKC) represents the major, high-affinity receptor for the phorbol esters as well as for a series of structurally diverse natural products. The phorbol esters function by binding to the tandem C1a and C1b domains in PKC, leading to enzyme activation. Although the typical phorbol esters represent the paradigm for tumor promoters in mouse skin, it is now clear that different high affinity ligands for PKC have distinct biological effects. Thus, the daphnane analogue mezerein is a second-stage promoter, the macrolide bryostatin 1 is a partial antagonist, and certain 12-deoxyphorbol 13-monoesters also function as partial antagonists but with a different pattern of activity. The biochemical basis for these differences is an area of active investigation. In this report, we have examined the relative interaction of ligands differing in structure and pattern of biological response with the C1a and C1b domains of PKC
. We mutated either or both of the C1 domains of PKC, expressed the constructs in NIH 3T3 cells, and monitored the interaction of the ligands by their ability to induce translocation of the mutated PKC from the cytosol to the particulate fraction. We found that different ligands showed different dependence on the C1a and C1b domains for translocation. Whereas phorbol 12-myristate 13-acetate and the indole alkaloids indolactam and octylindolactam were selectively dependent on the C1b domain, selectivity was not observed for mezerein, for the 12-deoxyphorbol 13-monoesters prostratin or 12-deoxyphorbol 13-phenylacetate, or for the macrocyclic lactone bryostatin 1. Provocatively, the pattern of response corresponds with the activity of the compounds as complete tumor promoters.
1 To whom requests for reprints should be addressed, at Molecular Mechanisms of Tumor Promotion Section, Laboratory of Cellular Carcinogenesis and Tumor Promotion, Building 37-3A01, National Cancer Institute, 37 Convent Drive MSC 4255, Bethesda, MD 20892-4255. Phone: (301) 496-3189; Fax: (301) 496-8709; E-mail: blumberp@dc37a.nci.nih.gov.
Received 10/21/97. Accepted 2/18/98.
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