The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response.
p53 is activated in response to various genotoxic stresses resulting in cell cycle arrest or apoptosis. It is well documented that DNA damage leads to phosphorylation and activation of p53 (refs 1-3), yet how p53 is activated is still not fully understood. Here we report that DNA damage specifically induces p53 phosphorylation on Ser/Thr-Pro motifs, which facilitates its interaction with Pin1, a member of peptidyl-prolyl isomerase. Furthermore, the interaction of Pin1 with p53 is dependent on the phosphorylation that is induced by DNA damage. Consequently, Pin1 stimulates the DNA-binding activity and transactivation function of p53. The Pin1-mediated p53 activation requires the WW domain, a phosphorylated Ser/Thr-Pro motif interaction module, and the isomerase activity of Pin1. Moreover, Pin1-deficient cells are defective in p53 activation and timely accumulation of p53 protein, and exhibit an impaired checkpoint control in response to DNA damage. Together, these data suggest a mechanism for p53 regulation in cellular response to genotoxic stress.
Zheng
Hongwu
H
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
You
Han
H
Zhou
Xiao Zhen
XZ
Murray
Stephen A
SA
Uchida
Takafumi
T
Wulf
Gerburg
G
Gu
Ling
L
Tang
Xiaoren
X
Lu
Kun Ping
KP
Xiao
Zhi-Xiong Jim
ZX
D020816:Amino Acid Motifs; D000818:Animals; D002453:Cell Cycle; D004249:DNA Damage; D005347:Fibroblasts; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009687:Nuclear Proteins; D019696:Peptidylprolyl Isomerase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse