Role of Pin1 in the regulation of p53 stability and p21 transactivation, and cell cycle checkpoints in response to DNA damage.
DNA damage leads to stabilization and accumulation of p53, which plays a pivotal role in transcriptional activation of p21 and cell cycle arrest. The increase in p53 stability depends critically on its phosphorylation on serine/threonine residues, including those preceding a proline (Ser(P)/Thr-Pro). The Ser(P)/Thr-Pro moiety exists in the two distinct cis and trans conformations and their conversion is catalyzed specifically by the prolyl isomerase Pin1. Pin1 regulates the conformation and function of certain phosphorylated proteins and plays an important role in cell cycle regulation, oncogenesis, and Alzheimer's disease. However, nothing is known about the role of Pin1 in DNA damage. Here we found that DNA damage enhanced the interaction between Pin1 and p53, which depended on the WW domain in Pin1 and Ser(33/46)-Pro motifs in p53. Furthermore, Pin1 regulates the stability of p53 and its transcriptional activity toward the p21 promoter. As a result, p53 and p21 barely increased after DNA damage in Pin1 knock-out embryonic fibroblasts or in neoplastic cells depleted of Pin1. Moreover, Pin1 null cells displayed significant defects in cell cycle checkpoints induced by DNA damage. These results demonstrate a new role of Pin1 in regulating p53 function during DNA damage.
Wulf
Gerburg M
GM
Cancer Biology Program, Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Liou
Yih-Cherng
YC
Ryo
Akihide
A
Lee
Sam W
SW
Lu
Kun Ping
KP
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D004249:DNA Damage; D006801:Humans; D051379:Mice; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D015533:Transcriptional Activation / Q000502:physiology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016159:Tumor Suppressor Protein p53; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse