tailieunhanh - Báo cáo khoa học: Structured DNA promotes phosphorylation of p53 by DNA-dependent protein kinase at serine 9 and threonine 18

Phosphorylation at multiple sites within the N-terminus of p53 promotes its dissociation from hdm2/mdm2 and sti-mulates its transcriptional regulatory potential. The large phosphoinositide 3-kinase-like kinases ataxia telangiectasia mutated gene product and the ataxia telangectasia and RAD-3-related kinase promote phosphorylation of human p53at Ser15andSer20, andare required for theactivationof p53 following DNA damage. DNA-dependent protein kin-ase (DNA-PK) is another large phosphoinositide 3-kinase-like kinase with the potential to phosphorylate p53 at Ser15, and has been proposed to enhance phosphorylation of these sites in vivo | Eur. J. Biochem. 271 3776-3784 2004 FEBS 2004 doi Structured DNA promotes phosphorylation of p53 by DNA-dependent protein kinase at serine 9 and threonine 18 Sébastien Soubeyrand1 Caroline Schild-Poulter1 and Robert J. G. Hache1 2 Departments of 1Medicine and 2Biochemistry Microbiology and Immunology University of Ottawa the Ottawa Health Research Institute Ottawa Ontario Canada Phosphorylation at multiple sites within the N-terminus of p53 promotes its dissociation from hdm2 mdm2 and stimulates its transcriptional regulatory potential. The large phosphoinositide 3-kinase-like kinases ataxia telangiectasia mutated gene product and the ataxia telangectasia and RAD-3-related kinase promote phosphorylation of human p53 at Ser15 and Ser20 and are required for the activation of p53 following DNA damage. DNA-dependent protein kinase DNA-PK is another large phosphoinositide 3-kinase-like kinase with the potential to phosphorylate p53 at Ser15 and has been proposed to enhance phosphorylation of these sites in vivo. Moreover recent studies support a role for DNA-PK in the regulation of p53-mediated apoptosis. We have shown previously that colocalization of p53 and DNA-PK to structured single-stranded DNA dramatically enhances the potential for p53 phosphorylation by DNA-PK. We report here the identification of p53 phosphorylation at two novel sites for DNA-PK Thr18 and Ser9. Colocalization of p53 and DNA-PK on structured DNA was required for efficient phosphorylation of p53 at multiple sites while specific recognition of Ser9 and Thr18 appeared to be dependent upon additional determinants of p53 beyond the N-terminal 65 amino acids. Our results suggest a role for DNA-PK in the modulation of p53 activity resultant from the convergence of p53 and DNA-PK on structured DNA. Keywords DNA-dependent protein kinase p53 structured single-stranded DNA phosphorylation. The large phosphatidylinositide 3-kinase PI3K -like kinases are broad specificity .

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