title: ATR controls the p21(WAF1/Cip1)  protein up-regulation and apoptosis in response to low UV fluences.
abstract: The universal cyclin-dependent kinase inhibitor p21(WAF1/Cip1)  promotes cell cycle arrest and inhibits apoptosis in response to UV-induced DNA damage. Since the protein kinase ATR plays a major role in the cellular response to these carcinogenic lesions, we investigated the possible role of ATR in the modulation of p21(WAF1/Cip1)  expression in response to UVC radiation. We have shown that p21(WAF1/Cip1)  is up-regulated in human fibroblast and epithelial cells, but only in response to low UV fluences and low passage cells. Importantly, this up-regulation is ATR-dependent. In fact, in ATR-deficient or caffeine-treated cells UV light rather down-regulated the p21(WAF1/Cip1)  protein through SKP2-dependent ubiquitination and degradation via the proteasomal pathway. Furthermore, we present evidence that ATR inhibits apoptosis in response to low fluences of UV light, through inhibiting the cleavage of caspase 3 and PARP as well as the repression of the proapoptotic proteins BAX and BAK. Interestingly, ATR is also required for the stability of the p21(WAF1/Cip1)  protein in absence of genotoxic stress. Together, these results indicate that during the cellular response to low UVC fluences the ATR protein kinase up-regulates p21(WAF1/Cip1)  and inhibits apoptosis. © 2011 Wiley Periodicals, Inc.
authors: King Faisal Specialist Hospital and Research Center, Department of Biological and Medical Research, Riyadh, KSA.
authors: Huda H
authors: HH
authors: Al-Khalaf
authors: Siti-Faujiah
authors: SF
authors: Hendrayani
authors: Abdelilah
authors: A
authors: Aboussekhra
mesh_terms: D017209:Apoptosis / Q000528:radiation effects*; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology*; D004307:Dose-Response Relationship, Radiation; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D054875:Ubiquitination; D014466:Ultraviolet Rays; D015854:Up-Regulation / Q000502:physiology / Q000528:radiation effects*
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases