Polo‐like kinase 1 regulates mitotic arrest after UV irradiation through dephosphorylation of p53 and inducing p53 degradation

Abstract

Ultraviolet (UV) irradiation can result in cell cycle arrest. The reactivation of Polo-like kinase 1 (Plk1) is necessary for cell cycle reentry. But the mechanism of how Plk1 regulates p53 in UV-induced mitotic arrest cells remained elusive. Here we find that UV treatment leads HEK293 cells to inverse changes of Plk1 and p53. Over-expression of Plk1 rescue UV-induced mitotic arrest cells by inhibiting p53 activation. Plk1 could also inhibit p53 phosphorylation at Ser15, thus facilitates its nuclear export and degradation. Further examination shows that Plk1, p53 and Cdc25C can form a large complex. Plk1 could bind to the sequence-specific DNA-binding domain of p53 and active Cdc25C by hyperphosphorylation. These results hypothesize that Plk1 and Cdc25C participate in recovery the mitotic arrest through binding to the different domain of p53. Cdc25C may first be actived by Plk1, and then its phosphatase activity makes p53 dephosphorylated at Ser15.

Inhibitory Role of Plk1 in the Regulation of p73-dependent Apoptosis through Physical Interaction and Phosphorylation

“…Similarly, Liu and Erikson (25) described that Plk1 depletion stabilizes p53 in HeLa cells. In support with this notion, Chen et al (36) found that Plk1 inhibits UV-mediated phosphorylation of p53 at Ser-15 and thereby facilitates its nuclear export and proteolytic degradation.…”

Polo-Like Kinase 1: Target and Regulator of Transcriptional Control

“…Cdc25C, a phosphatase known to be activated by Plk1-dependent phosphorylation, seems to mediate the Plk1-induced dephosphorylation of p53, since Cdc25C is found in a complex with Plk1 and p53 in HEK293 cells. 40 In light of the data reviewed within this article, Plk1 contributes to the regulation of its own gene expression by the ability to render p53 inactive.…”

“…39 In contrast, overexpression of Plk1 decreases the Ser 15 phosphorylation level of p53 in UV-induced M-phase arrested HEK293 cell. 40 Since phosphorylation of Ser 15 contributes to increased stability of the p53 protein, this scenario also results in inactivation of p53 by Plk1. Cdc25C, a phosphatase known to be activated by Plk1-dependent phosphorylation, seems to mediate the Plk1-induced dephosphorylation of p53, since Cdc25C is found in a complex with Plk1 and p53 in HEK293 cells.…”

“…[39][40][41] Interestingly, the transcriptional activity and subsequently the apoptotic function of the tumor suppressor protein p53 are hindered by Plk1. This inhibition is mediated most likely via a physical interaction of both proteins, since the kinase domain of Plk1 interacts directly with the sequence-specific DNA-binding domain of p53 in COS7 cells as well as in HEK293 cells.…”

“…This inhibition is mediated most likely via a physical interaction of both proteins, since the kinase domain of Plk1 interacts directly with the sequence-specific DNA-binding domain of p53 in COS7 cells as well as in HEK293 cells. 39,40 Expression of Plk1 decreases p53-mediated transcription of p53-responsive p21 WAF1 -, MDM2-or BAX-luciferase reporter constructs. Furthermore, Plk1 blocks expression of endogenous p21 WAF1 .…”