Impaired jun-NH2-terminal kinase activation by ultraviolet irradiation in fibroblasts of patients with Cockayne syndrome complementation group B.
c-jun-NH2 kinases (JNK) are among the UV-activated protein kinases that play an important role in cellular stress response via the phosphorylation of c-jun, ATF2, and p53. Activation of JNK by UV irradiation requires cooperation between membrane and nuclear components, including DNA lesions per se. The role of DNA lesions in JNK activation led us to explore the inducibility of these kinases in cells of repair-deficient patients. Analyses of primary fibroblast cell lines from patients with Cockayne Syndrome of complementation group B (CS-B) revealed poor JNK activation after UV irradiation in four of five cases when compared with three repair-proficient, normal human fibroblast cell lines. Impaired ability to activate JNK persisted at various time points and with different doses of UV irradiation and coincided with failure of in vitro damaged DNA to activate these kinases. In contrast to UV irradiation, other forms of stress, such as H2O2 or heat shock were capable of inducing JNK activation in CS-B cells. Interestingly, when UV irradiation was administered after osmotic shock, it led to JNK activation in CS-B cells, indicating that alternate signal transduction pathways that are activated in response to other forms of stress can potentiate JNK activation by UV irradiation. Unlike CS-B cells, those of other repair-deficient cells, including xeroderma pigmentosum of different complementation groups, revealed proper activation of JNK by UV irradiation. Together, our findings point to deficiency of JNK activation by UV irradiation in CS-B cells, a phenomenon which may be associated with impaired CS-B, the mutant repair gene in these patients.
Dhar
V
V
Molecular Carcinogenesis Program, American Health Foundation, Valhalla, New York 10595, USA.
Adler
V
V
Lehmann
A
A
Ronai
Z
Z
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis / Q000528:radiation effects*; D002460:Cell Line; D003057:Cockayne Syndrome / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D004249:DNA Damage; D004260:DNA Repair; D004789:Enzyme Activation; D004790:Enzyme Induction; D005347:Fibroblasts / Q000201:enzymology / Q000528:radiation effects; D005816:Genetic Complementation Test; D006358:Hot Temperature; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D009997:Osmotic Pressure; D013312:Stress, Physiological / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D014466:Ultraviolet Rays
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases