The Phosphatase MKP1 Is a Transcriptional Target of p53 Involved in Cell Cycle Regulation

Abstract

The tumor suppressor p53 protein suppresses cell growth by inducing cell cycle arrest or apoptosis. Despite the fact that p53-dependent p21-mediated G 1 arrest induced by DNA damage is well defined, the role of p53 in the cell cycle in response to the MAKP signaling remains to be determined. Here we show that MKP1, a member of the dual specificity protein phosphatase family capable of inactivating MAPKs, is a transcriptional target of p53. MKP1 mRNA and protein levels were increased upon p53 activation in several well defined p53-regulated cell systems. p53 bound to a consensus p53 binding site located in the second intron of the MKP1 gene and transactivated MKP1 in reporter gene assays. Inhibition of phosphatase activity impaired p53-mediated G 1 arrest in arrested human glioblastoma GM cells in response to growth factor stimuli. Importantly conditional expression of MKP1 prevented arrested human cancer cells from entering into the cell cycle. Thus, these results provide a novel mechanism by which p53 controls the cell cycle in response to the MAPK signaling in the absence of DNA damage and suggest that p53 may negatively control the MAKP pathway via MKP1.

Regulation of the phosphorylation and integrity of protein synthesis initiation factor eIF4GI and the translational repressor 4E-BP1 by p53

“…This is suggested by the rapid decrease in the extent of phosphorylation of Ser 64 in vivo (Figure 1b) at a time when there is only a modest inhibition of protein kinase activity directed towards this site in in vitro assays (Figure 7b). Recently, several reports have shown that p53 is able to induce or activate novel protein phosphatases (Li et al, 2003;Ueda et al, 2003;Yin et al, 2003) but whether any of these act on 4E-BP1 remains to be established. It may be significant that the greatest p53-induced loss of phosphate from 4E-BP1 in vivo appears to involve Ser 64 , since this site can have a large influence on the binding of the protein to eIF4E (Mothe-Satney et al, 2000b;Karim et al, 2001) (although this conclusion has been challenged; Ferguson et al, 2003).…”

PBK/TOPK interacts with the DBD domain of tumor suppressor p53 and modulates expression of transcriptional targets including p21

“…Expression levels of at least nine p53 target genes involved in cell-cycle regulation and/or apoptosis were also significantly altered by PBK knockdown. Among these were p21 (Bunz et al, 1998;Wendt et al, 2006), DUSP1 (Li et al, 2003) PBK/TOPK and p53 functional interactions F Hu et al (Pohl et al, 1999), FAS (Mu¨ller et al, 1998;Pohl et al, 1999), CASP10 (Rikhof et al, 2003) (all upregulated), and Bcl-xL (Bartke et al, 2001), which was downregulated. G2E3 (Brooks et al, 2007(Brooks et al, , 2008, a newly characterized gene involved in G 2 /M cell-cycle progression, was found to be suppressed by PBK knockdown, but its association to p53 is unknown.…”

The dark side of a tumor suppressor: anti-apoptotic p53

“…Also MKP1, the founding member of the dual-specificity protein phosphatase family, was found to be a direct transcriptional target of p53. 46 Functional studies revealed a marked influence of this phosphatase on p53-mediated cell cycle arrest. Whereas inhibition of its phosphatase activity by vanadate impaired p53-mediated G1-arrest in human glioblastoma cells in response to growth factor stimuli, conditional expression of MKP1 prevented arrested human lung cancer cells from entering into the cell cycle.…”