Transforming growth factor-beta enhances the ultraviolet-mediated stress response in p53-/- keratinocytes.
Skin cancer is the most common tumor type in Caucasians, with an incidence that approaches the lifetime risk for all other cancer subtypes combined. 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 phosphorylation of c-Jun, all of which are part of the cellular stress response. Transforming growth factor-beta1 (TGF-beta1) is an important negative regulator of keratinocyte proliferation and has other pleiotropic effects in these cells. The purpose of these investigations was to decide whether TGF-beta1 activated c-Jun amino-terminal kinases in a spontaneously immortalized human keratinocyte cell line, HaCaT, and if TGF-beta1 modulated the activation of JNK in keratinocytes exposed to ultraviolet C (UVC) radiation. Results from these investigations showed that TGF-beta1 (10 ng/ml) activated JNK within 5 min. Pretreatment with TGF-beta1 enhanced UV-mediated JNK activation and was time- and UV-dose-dependent. Pretreatment with TGF-beta1 also enhanced activity of the c-Jun promoter-reporter construct, TRE(x5)-CAT. These results suggested that TGF-beta1 modulates the response of keratinocytes to ultraviolet radiation and implicates TGF-beta1 as a potential mediator the cellular of stress response in keratinocytes.
Merryman
J I
JI
The University of Tennessee College of Veterinary Medicine, Knoxville, TN 37996, USA.
Neilsen
N
N
Stanton
D D
DD
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D020928:Mitogen-Activated Protein Kinases; D009154:Mutation; D004676:Myelin Basic Protein / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases
D004676:Myelin Basic Protein; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D015500:Chloramphenicol O-Acetyltransferase; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases