TRANSFORMING GROWTH FACTOR-BETA(1) ENHANCES THE ULTRAVIOLET-MEDIATED STRESS-RESPONSE IN P53(- -) KERATINOCYTES/

Skin cancer is the most common tumor type in Caucasians, with an incid ence that approaches the lifetime risk for all other cancer subtypes c ombined. The most common predisposing factor in the development of non -melanoma skin cancer is exposure to ultraviolet (UV) radiation in sun light. UV radiation activates c-Jun amino-terminal kinases (JNK): this kinase pathway is involved in UV-mediated apoptosis and phosphorylati on of c-jun, all of which are part of the cellular stress response. Tr ansforming growth factor-beta(1) (TCF-beta(1)) is an important negativ e regulator of keratinocyte proliferation and has other pleiotropic ef fects in these cells. The purpose of these investigations was to decid e whether TGF-beta(1) activated c-Jun amino-terminal kinases in a spon taneously immortalized human keratinocyte cell line, HaCaT, and if TGF -beta(1) modulated the activation of JNK in keratinocytes exposed to u ltraviolet C (UVC) radiation. Results from these investigations showed that TGF-beta(1) (10 ng/ml) activated JNK within 5 min. Pretreatment with TGF-beta(1) enhanced UV-mediated JNK activation and was time- and UV-dose-dependent. Pretreatment with TGF-beta(1) also enhanced activi ty of the c-Jun promoter-reporter construct, TRE(x5)-CAT. These result s suggested that TGF-beta(1) modulates the response of keratinocytes t o ultraviolet radiation and implicates TGF-beta(1) as a potential medi ator of the cellular stress response in keratinocytes.