Expression Profiling of UVB Response in Melanocytes Identifies a Set of p53-Target Genes

Abstract

Epidermal melanocytes execute specific physiological programs in response to UV radiation (UVR) at the cutaneous interface. Many melanocytic responses, including increased dendrite formation, enhanced melanogenesis/melanization, and cell cycle arrest impact the ability of melanocytes to survive and to attenuate the UVR insult. Although some of the molecules that underlie these UVR programs are known, a coherent view of UVR-induced transcriptional changes is lacking. Using primary melanocyte cultures, we assessed for UVR-mediated alterations in over 47,000 transcripts using Affymetrix Human Genome U133 Plus 2.0 microarrays. From the 100 most statistically robust changes in transcript level, there were 84 genes that were suppressed >2.0-fold by UVR; among these transcripts, the identities of 48 of these genes were known. Similarly, there were 99 genes that were induced >2.0-fold by UVR; the identity of 57 of these genes were known. We then subjected these top 100 changes to the Ingenuity Pathway analysis program and identified a group of p53 targets including the cell cycle regulator CDKN1A (p21CIP), the WNT pathway regulator DKK1 (dickkopf homolog 1), the receptor tyrosine kinase EPHA2, growth factor GDF15, ferrodoxin reductase (FDXR), p53-inducible protein TP53I3, transcription factor ATF3, DNA repair enzyme DDB2, and the beta-adrenergic receptor ADBR2. These genes were also found to be consistently elevated by UVR in six independent melanocyte lines, although there were interindividual variations in magnitude. WWOX, whose protein product interacts and regulates p53 and p73, was found to be consistently suppressed by UVR. There was also a subgroup of neurite/axonal developmental genes that were altered in response to UVR, suggesting that melanocytic and neuronal arborization may share similar mechanisms. When compared to melanomas, the basal levels of many of these p53-responsive genes were greatly dysregulated. Three genes--CDKN1A, DDB2 and ADRB2--exhibited a trend towards loss of expression in melanomas thereby raising the possibility of a linked role in tumorigenesis. These expression data provide a global view of UVR-induced changes in melanocytes and, more importantly, generate novel hypotheses regarding melanocyte physiology.