Dose-dependent mutual regulation between Wip1 and p53 following UVC irradiation

Abstract

DNA damage stabilizes and activates p53, which selectively induces downstream targets to modulate the cellular response. As a homeostatic regulator of cell cycle checkpoint, the p53 target Wip1 plays essential roles in releasing cells from DNA damage-induced checkpoints after appropriate repair of the damaged-DNA. It is unknown how Wip1 performs when the DNA damage is beyond repair. Here we address that Wip1 displays dose-dependent responses to UVC irradiation. A low dose of UVC, which stimulates intra-S phase cell cycle arrest, transiently induces the Wip1 protein levels in a p53-dependent manner. In contrast, a high dose of UVC, which induces apoptosis, suppresses the Wip1 protein levels in a p53-independent manner. The UVC dose-dependent response of Wip1 correlates not only with the cellular response but also with the activity of p53. Wip1 dephosphorylates p53 on its Ser15 residue. However, the mutual regulation between Wip1 and p53 is only triggered by a low dose of UVC. In response to a high dose of UVC, the sustained activation of p53 fails to induce the downstream targets, including Wip1, Mdm2, p21 and GADD45α. Nonetheless, the reduced Wip1 level contributes to the sustained accumulation of phospho-p53 (Ser15) in response to a high dose of UVC. Our results suggest that Wip1 is regulated by UVC in a dose-dependent manner. Moreover, the mutual regulation between Wip1 and p53 is highly dose-dependent upon UVC irradiation, and this contributes to the different outcomes of the cellular response to UVC. © 2010 Elsevier Ltd. All rights reserved.