RNA FINGERPRINTING DISPLAYS UVB-SPECIFIC DISRUPTION OF TRANSCRIPTIONAL CONTROL IN HUMAN MELANOCYTES

In mammalian cells, UV induces a limited set of early transcribed gene s, which overlaps with the set of genes induced by tumor promoting dru gs such as 12-O-tetradecanoyl phorbol-13-acetate (TPA). Among these ar e genes for transcription factors, the activation of which leads to co mplex secondary changes in expression of multiple target genes. How th ese delayed pleiotropic UV effects on transcription may contribute to initiation of melanoma skin cancer is poorly understood, We anal;zed c hanges in the relative abundances of 1900 transcripts in newborn human melanocytes 8 h after treatment with UVB, TPA, and cycloheximide in a ll combinations, using RNA arbitrarily primed PCR for differential dis play. The relative abundances of 205 transcripts (11% of all transcrip ts surveyed) were altered by one or more of the treatment combinations , Fourteen of the 77 genes up-regulated by TPA were also up-regulated by UVB, but 60 of the TPA up-regulated genes were down-regulated by UV B, indicating both intersecting and independent signal transduction pa thways for UVB and TPA. A number of UVB and TPA target genes were iden tified by cDNA cloning, Consistent with UVB induction of a partly tran sformed phenotype in mammalian cells, UVB antagonized the TPA-inducibl e expression of tumor-suppressive tropomyosin 3 mRNA. In addition, UVB may impair mitochondrial Functioning and induce oxidative stress by s trong down-regulation of mitochondrial transcription. Finally, increas ed expression of the dihydropteridine reductase gene, a major regulato r of the cellular tetrahydrobiopterin pool, was linked to the UV pathw ay.