10. Wip1 Activity and Regulation of Expression
Wip1 phosphatase is a critical protein regulating the DNA damage repair processes. Following DNA damage repair, the homeostatic mechanisms of the cell require Wip1 activity to release cells from cell cycle arrest, by dephosphorylating and thus inactivating p53, p38 MAPK, ataxia telangiectasia mutated (ATM) and other stress induced proteins (for review of Wip1 targets, refer to J. Lowe et al., 2013) [91]. With p53 no longer inducing cell cycle arrest, the cell is able to return to its original unphosphorylated state.
The PPM1D/Wip1 gene was originally discovered as a p53-induced gene. However, it has since been discovered that its expression depends also on many other stress-induced transcription factors apart from p53. Mainly, its product, Wip1, provides a negative feedback loop for the activity of many DNA repair factors including the dephosphorylation, and thus inactivation, of histone 2HX-γ (H2AX-γ), and p53 regulating (inhibitor) molecules [74,92].
Furthermore, the over-expression of Wip1 negatively regulates the NF-κB response by reducing TNF-α induced phosphorylation of the serine 536 of p65 and reducing its binding with p300. The effects of Wip1 activity on inhibition of NF-κB and chromatin remodeling are independent of p38 MAPK pathway activation [93]. Notably, Wip1 expression is decreased when NF-κB activity is inhibited in primary astrocytes, indicating a positive regulation of NF-κB on the PPM1D gene and, further on, the neuroinflammatory regulation by Wip1 and NF-κB inhibition [84].
Wip1 expression is reduced during neutrophil activation and is directly inhibited by the increase of microRNA-16 expression which targets its 3’ untranslated region and thus regulates post-transcriptionally Wip1 translation. Finally, the TLR4 ligands, and the activation of inflammatory cytokines, downregulate Wip1 expression via the activation of microRNA-16 by p38 MAPK and NF-κB [76,94].