The Wip1 Phosphatase PPM1D Dephosphorylates SQ/TQ Motifs in Checkpoint Substrates Phosphorylated by PI3K-like Kinases†

Biochemistry ◽  
2007 ◽  
Vol 46 (44) ◽  
pp. 12594-12603 ◽  
Author(s):  
Hiroshi Yamaguchi ◽  
Stewart R. Durell ◽  
Deb K. Chatterjee ◽  
Carl W. Anderson ◽  
Ettore Appella
Keyword(s):  
Wip1 Phosphatase

scholarly journals WIP1 Inhibition by GSK2830371 Potentiates HDM201 through Enhanced p53 Phosphorylation and Activation in Liver Adenocarcinoma Cells

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3876
Author(s):  
Chiao-En Wu ◽  
Chen-Yang Huang ◽  
Chiao-Ping Chen ◽  
Yi-Ru Pan ◽  
John Wen-Cheng Chang ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Primary Liver Cancer ◽  
P53 Protein ◽  
Intrahepatic Bile Duct ◽  
Cell Cycle Distribution ◽  
P53 Signaling ◽  
Adenocarcinoma Cells ◽  
Wip1 Phosphatase ◽  
P53 Activation ◽  
Novel Strategy

Background: Intrahepatic cholangiocarcinoma (iCCA) is an adenocarcinoma arising from the intrahepatic bile duct. It is the second most common primary liver cancer and has a poor prognosis. Activation of p53 by targeting its negative regulators, MDM2 and WIP1, is a potential therapy for wild-type p53 cancers, but few reports for iCCA or liver adenocarcinoma exist. Methods: Both RBE and SK-Hep-1 liver adenocarcinoma cell lines were treated with the HDM201 (Siremadlin) MDM2-p53 binding antagonist alone or in combination with the GSK2830371 WIP1 phosphatase inhibitor. Cell proliferation, clonogenicity, protein and mRNA expression, cell cycle distribution, and RNA sequencing were performed to investigate the effect and mechanism of this combination. Results: GSK2830371 alone demonstrated minimal activity on proliferation and colony formation, but potentiated growth inhibition (two-fold decrease in GI50) and cytotoxicity (four-fold decrease in IC50) by HDM201 on RBE and SK-Hep-1 cells. HDM201 increased p53 protein expression, leading to transactivation of downstream targets (p21 and MDM2). Combination with GSK2830371 increased p53 phosphorylation, resulting in an increase in both p53 accumulation and p53-dependent trans-activation. G2/M arrest was observed by flow cytometry after this treatment combination. RNA sequencing identified 21 significantly up-regulated genes and five downregulated genes following p53 reactivation by HDM201 in combination with GSK2830371 at 6 h and 24 h time points compared with untreated controls. These genes were predominantly known transcriptional targets regulated by the p53 signaling pathway, indicating enhanced p53 activation as the predominant effect of this combination. Conclusion: The current study demonstrated that GSK2830371 enhanced the p53-dependent antiproliferative and cytotoxic effect of HDM201 on RBE and SK-Hep-1 cells, providing a novel strategy for potentiating the efficacy of targeting the p53 pathway in iCCA.

scholarly journals PPM1D is a neuroblastoma oncogene and therapeutic target in childhood neural tumors

2020 ◽  
Author(s):  
Jelena Milosevic ◽  
Susanne Fransson ◽  
Miklos Gulyas ◽  
Gabriel Gallo-Oller ◽  
Thale K Olsen ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Genetic Manipulation ◽  
Clonal Evolution ◽  
Neuroblastoma Cell ◽  
Tumor Formation ◽  
T Cell Lymphomas ◽  
Wip1 Phosphatase ◽  
Bona Fide ◽  
Genome Scale

SUMMARYMajority of cancers harbor alterations of the tumor suppressor TP53. However, childhood cancers, including unfavorable neuroblastoma, often lack TP53 mutations despite frequent loss of p53 function, suggesting alternative p53 inactivating mechanisms.Here we show that p53-regulating PPM1D at chromosome 17q22.3 is linked to aggressive tumors and poor prognosis in neuroblastoma. We identified that WIP1-phosphatase encoded by PPM1D, is activated by frequent segmental 17q-gain further accumulated during clonal evolution, gene-amplifications, gene-fusions or gain-of-function somatic and germline mutations. Pharmacological and genetic manipulation established WIP1 as a druggable target in neuroblastoma. Genome-scale CRISPR-Cas9 screening demonstrated PPM1D genetic dependency in TP53 wild-type neuroblastoma cell lines, and shRNA PPM1D knockdown significantly delayed in vivo tumor formation. Establishing a transgenic mouse model overexpressing PPM1D showed that these mice develop cancers phenotypically and genetically similar to tumors arising in mice with dysfunctional p53 when subjected to low-dose irradiation. Tumors include T-cell lymphomas harboring Notch1-mutations, Pten-deletions and p53-accumulation, adenocarcinomas and PHOX2B-expressing neuroblastomas establishing PPM1D as a bona fide oncogene in wtTP53 cancer and childhood neuroblastoma. Pharmacological inhibition of WIP1 suppressed the growth of neural tumors in nude mice proposing WIP1 as a therapeutic target in neural childhood tumors.

Wip1 phosphatase deficiency impairs spatial learning and memory

2020 ◽  
Vol 533 (4) ◽  
pp. 1309-1314
Author(s):  
Si-Cheng Liu ◽  
Ming Zhang ◽  
Ping Gan ◽  
Hao-Fei Yu ◽  
Cai-Feng Ding ◽  
...  
Keyword(s):  
Learning And Memory ◽  
Spatial Learning ◽  
Spatial Learning And Memory ◽  
Wip1 Phosphatase

scholarly journals Wip1 Phosphatase Regulates p53-Dependent Apoptosis of Stem Cells and Tumorigenesis in the Mouse Intestine

2007 ◽  
Vol 1 (2) ◽  
pp. 180-190 ◽  
Author(s):  
Oleg N. Demidov ◽  
Oleg Timofeev ◽  
Hnin N.Y. Lwin ◽  
Calvina Kek ◽  
Ettore Appella ◽  
...  
Keyword(s):  
Stem Cells ◽  
Wip1 Phosphatase ◽  
Mouse Intestine

WIP1 phosphatase is a negative regulator of NF-κB signalling

2009 ◽  
Vol 11 (5) ◽  
pp. 659-666 ◽  
Author(s):  
Joanne Chew ◽  
Subhra Biswas ◽  
Sathyavageeswaran Shreeram ◽  
Mahathir Humaidi ◽  
Ee Tsin Wong ◽  
...  
Keyword(s):  
Negative Regulator ◽  
Wip1 Phosphatase

Timely Degradation of Wip1 Phosphatase by APC/C Activator Protein Cdh1 is Necessary for Normal Mitotic Progression

2015 ◽  
Vol 116 (8) ◽  
pp. 1602-1612 ◽  
Author(s):  
Ho-Chang Jeong ◽  
Na-Yeon Gil ◽  
Ho-Soo Lee ◽  
Seung-Ju Cho ◽  
Kyungtae Kim ◽  
...  
Keyword(s):  
Mitotic Progression ◽  
Activator Protein ◽  
Wip1 Phosphatase

Wip1 Phosphatase Involved in Lipopolysaccharide-Induced Neuroinflammation

2013 ◽  
Vol 51 (3) ◽  
pp. 959-966 ◽  
Author(s):  
Xiang Tan ◽  
Jingjing Zhang ◽  
Wei Jin ◽  
Lei Li ◽  
Wei Xu ◽  
...  
Keyword(s):  
Wip1 Phosphatase
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