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Papers In Press, published online ahead of print October 17, 2002
Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215
Corresponding Author: klu{at}caregroup.harvard.edu
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 (pSer/Thr-Pro). The pSer/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 Ser33/46-Pro motifs in p53. Furthermore, Pin1 regulates the stability of p53 and its transcriptional activity towards the p21 promoter. As a result, p53 and p21 barely increased after DNA damage in Pin1 knockout 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.
J. Biol. Chem, 10.1074/jbc.C200538200
Submitted on September 22, 2002
Revised on October 6, 2002
Accepted on October 16, 2002
Role of Pin1 in the regulation of p53 stability and p21 transactivation, and cell cycle checkpoints in response to DNA damage
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