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Symposium: Advances in Retinoid Research: Mechanisms of Cancer Chemoprevention

Vitamin A (Retinoids) Regulation of Mouse Melanoma Growth and Differentiation^1,2

Department of Biochemistry and Molecular Biology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25704

³To whom correspondence should be addressed. E-mail: niles{at}marshall.edu.

The incidence of melanoma is rapidly increasing in the U.S. population. At the present, there is no effective chemotherapy against invasive melanoma. At our laboratory, we have been studying retinoic acid (RA)-induced growth arrest and differentiation in the B16 murine melanoma cell model. Several immediate-early gene targets of RA were identified by gene arrays. In one of these genes, T-box binding protein-2 (Tbx-2), an RA response element, was identified in the promoter region that mediates the RA responsiveness of this gene. RA also induces a sixfold to eightfold increase in protein kinase C (PKC) RNA and protein. This gene is not a direct target of RA but appears to be required for the biological effects of RA in B16 melanoma cells. PKC can alter gene transcription via phosphorylation of activator protein (AP)-1. RA increased AP-1 activity in B16 cells but with delayed kinetics compared with activation of PKC by phorbol dibutyrate. Clones stably expressing a dominant negative A-fos gene had reduced AP-1 activity and were less sensitive to RA induction of growth arrest and differentiation. Paradoxically, although inhibition of PKC enzyme activity blocked phorbol dibutyrate-stimulated AP-1 activity, it had no effect on RA-induced AP-1 activity. Further investigation showed that PKC enzyme activity was not required for RA-induced growth inhibition or stimulation of melanin synthesis. These data suggest that PKC either works through a nonenzymatic protein-protein mechanism or may interfere with the enzymatic function of another isozyme of PKC to mediate the actions of RA in B16 melanoma cells.

KEY WORDS: • protein kinase C • activator protein (AP)-1 • melanoma cells • retinoic acid

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