Abstract B52: The role of p38 activation in nucleotide excision repair in human skin

Abstract

Abstract Keratinocyte-based skin malignancies are diagnosed over one million times a year in this country alone despite widespread knowledge about UV avoidance and sunscreen use. The majority bear evidence of UV-induced mutations in key cancer-related genes such as TP53, highlighting the importance of environmental sun and tanning bed exposure in their pathophysiology. Accumulation of UV-induced DNA mutations, and ultimately skin cancer risk, is determined not only by UV exposure but also by the ability of keratinocytes to repair mutagenic damage caused by UV radiation. Xeroderma pigmentosum patients, in whom DNA repair is defective due to homozygous loss of any one of at least eight enzymes in the nucleotide excision repair (NER) pathway, suffer exceptionally high incidences of UV-induced skin cancers, illustrating the importance of NER in resistance to skin cancer. There is little understanding of the factors that determine the efficiency of NER in the skin. We have found that NER can be modified exogenously by inducing a cAMP-based pathway in the skin. Specifically, topically-applied forskolin, an activator of adenylate cyclase reproducibly enhances clearance of UV-induced cyclobutane dimers in human skin explants and in human keratinocytes. Pharmacologic induction of cAMP via forskolin efficiently activates the protein kinase A (PKA) signaling cascade and leads to downstream phosphorylation of the cAMP responsive binding element (CREB) transcription factor. Intriguingly, we and others have found that UV radiation also results in robust CREB phosphorylation in human skin and human keratinocytes, but in a PKA-independent manner. Furthermore, UVB induced CREB phosphorylation displays similar kinetics to UVB induced p38 activation and is diminished upon p38 inhibition. Together, these data suggests the p38 damage response pathway, recruited by UV, directly phosphorylates CREB without involving the cAMP second messenger. Currently, we are determining the effects of p38 inhibition on NER activity. We hypothesize that inhibiting p38 will lead to decreased NER activity in human skin and this loss of NER can be overcome with the addition of forskolin. Our observations presented here suggest that the p38/CREB signaling axis may be a major determinant of NER efficiency in the skin and raise the exciting possibility of a novel skin cancer preventative approach outside of UV-avoidance. Citation Information: Cancer Prev Res 2011;4(10 Suppl):B52.