29th Annual Meeting of the American Society of Photobiology

Downtown Marriot

Chicago, Il.

Melanogenesis and BRCA1 Signaling Pathways are Similar After UV Irradiation and Treatment with Bicyclic Monoterpene Diols

Abstract-
We have shown that similar to UV irradiation, bicyclic monoterpene (BMT) diols induce melanogenesis in cultured cells and animal skin via the nitric oxide/cGMP/PKG signaling pathway. Induction of melanogenesis in S91 mouse melanoma cells by 250 to 500 M 2,3-cis/exo-pinanediol results in a 20-25% reduction of CPDs following subsequent irradiation with 125 J/m² UVB. Novel BMT diols have now been synthesized that are an order of magnitude more potent inducers of melanogenesis than 2,3-cis/exo-pinanediol in cultured cells and human skin. When tested up to 5 mM, BMT diols are not mutagenic in either shuttle vector or HPRT genomic mutation assays. In addition to similar effects on nitric oxide signaling, both UVB and BMT diols stimulate phosphorylation of BRCA1 in human keratinocytes. The phosphorylated form of BRCA1 is known to be associated with its DNA repair and tumor suppressor properties. Thus, increased photoprotection by BMT diols may be due to both increased melanin and increased DNA repair. Rapamycin inhibits UVB- or BMT diol-induced phosphorylation of BRCA1, suggesting signaling mediated by a FRAP-dependent pathway. Thus, nitric oxide/cGMP/PKG and FRAP may constitute common signaling pathways for UVR and BMT diols.

Keywords: melanin, DNA repair, BRCA1, FRAP