Regulation of the Wip1 phosphatase and its effects on the stress response

Abstract

Wip1 (PPM1D) is a stress responsive PP2C phosphatase that plays a key role in stress signaling. Although originally identified as a gene induced by p53 after genotoxic stress, we now know that Wip1 expression is additionally regulated by other mechanisms. Wip1 is not only a target of p53, but is also a target of other transcription factors, including Estrogen Receptor-alpha and NF-kappaB. Additionally, Wip1 expression is regulated by post-transcriptional mechanisms such as mRNA stabilization and alternative splicing. Upon induction, Wip1 dampens the stress response by dephosphorylating and inactivating proteins such as p53, p38 MAPK, and ATM, usually as part of a negative feedback loop. As a result, Wip1 functions to abrogate cell cycle checkpoints and inhibit senescence, apoptosis, DNA repair, and the production of inflammatory cytokines. Furthermore, Wip1 is overexpressed in several types of human cancers and has oncogenic functions. The regulation of Wip1, the role of Wip1 in stress signaling, and the cooperation of Wip1 with oncogenes in promoting tumorigenesis will be discussed in this review.

Figure 1

Transcription factor binding sites in the PPM1D promoter. A schematic of the PPM1D promoter region shows the location of the transcription factor binding sites (based on the NCBI March 2006 human reference sequence Build 36.1). A list of the transcription factors and the location and the sequence of the respective binding site is shown.

Figure 2

Transcriptional regulation of PPM1D. The currently known transcription factors that enhance PPM1D transcription are p53, CREB, E2F1, c-jun, ERalpha, and NF-kappaB. The regulation by each of these factors depends on context, namely the type of stress and possibly the tissue type (see text for details).

Figure 3

Regulation of Wip1 expression: emphasis on post-transcriptional mechanisms. The four mechanisms of post-transcriptional modulation of Wip1 expression are depicted. After DNA damage, BRCA1-IRIS enhances the expression of HuR, which stabilizes Wip1 mRNA leading to enhanced Wip1 expression. IR-induced miR-16 destabilizes Wip1 mRNA and decreases Wip1 expression. The Wip1 transcript is alternatively spliced to form a shorter variant (“PPM1D430”), which leads to an enhanced expression of a smaller Wip1 protein (“Wip1^s”) that localizes to the nucleus, cytoplasm and plasma membrane. IR induces a p53-dependent shift in the transcriptional start site (“TSS”) of PPM1D, which produces a shorter transcript allowing for more efficient export from the nucleus.

Figure 4

The targets and functional consequences of Wip1 signaling. Wip1 signals through direct dephosphorylation of target proteins, which prevents apoptosis, inhibits DNA repair, reverses cell cycle arrest, and reduces inflammation. The proteins highlighted in red suppress tumorigenesis, and Wip1 inhibition of these proteins promotes tumorigenesis. *p53 and p38 MAPK enhance the tumor suppressor effects of p16^Ink4a/p19^Arf.

Figure 5

Model of stem cell self-renewal under normal and cancerous conditions. Stem cells normally remain quiescent due to strong anti-growth control from their surrounding microenvironment, termed a niche. A transient proliferation signal stimulates self-renewal to support tissue regeneration. Maintenance of stemness is promoted by Wip1. Under cancerous conditions, internal mutations and alteration of the microenvironment promote abnormal self-renewal of stem cells favoring growth. Unless tumor suppressors detect such an abnormality, cancerous stem cells (CSCs) or cancer initiating cells (TICs) may be generated from stem cells after a secondary genetic mutation. The proliferation of CSCs or TICs may be promoted by overexpression of Wip1.

Figure 6

Wip1 negative feedback in inflammatory signaling. Schematic adapted from (6). Wip1 expression is induced by NF-kappaB. Wip1 inhibits production of TNFalpha by dephosphorylating and inhibiting the NF-kappaB subunit p65 (highlighted in green) and inhibits IL-6 and IL-8 production through p38 MAPK (highlighted in purple).