DNA damage-induced phosphatase Wip1 in regulation of hematopoiesis, immune system and inflammation

Uyanik, Burhan; Grigorash, Bogdan B.; Goloudina, Anastasia R.; Demidov, Oleg N.

doi:10.1038/cddiscovery.2017.18

Cited by 40 publications

(29 citation statements)

References 43 publications

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“…Besides well-established roles of WIP1 in regulation of stress response pathways, there is emerging evidence implicating WIP1 in differentiation of hematopoietic progenitors and in the immune response (recently reviewed in [ 120 , 121 ]). In particular, PPM1D knock-out mice show a p53-dependent block in T cell and B cell maturation in the thymus and bone marrow, respectively [ 122 , 123 ].…”

Section: Role Of Wip1 In Immune Response and Hematopoiesismentioning

confidence: 99%

WIP1 phosphatase as pharmacological target in cancer therapy

2017

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DNA damage response (DDR) pathway protects cells from genome instability and prevents cancer development. Tumor suppressor p53 is a key molecule that interconnects DDR, cell cycle checkpoints, and cell fate decisions in the presence of genotoxic stress. Inactivating mutations in TP53 and other genes implicated in DDR potentiate cancer development and also influence the sensitivity of cancer cells to treatment. Protein phosphatase 2C delta (referred to as WIP1) is a negative regulator of DDR and has been proposed as potential pharmaceutical target. Until recently, exploitation of WIP1 inhibition for suppression of cancer cell growth was compromised by the lack of selective small-molecule inhibitors effective at cellular and organismal levels. Here, we review recent advances in development of WIP1 inhibitors and discuss their potential use in cancer treatment.

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Section: Role Of Wip1 In Immune Response and Hematopoiesismentioning

confidence: 99%

WIP1 phosphatase as pharmacological target in cancer therapy

2017

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“…WIP1 is a homeostatic regulator of the DNA damage response (DDR) cascade by dephosphorylating and inactivation of ATM, ATR, CHK1, CHK2 and DNA-dependent protein kinase catalytic subunit 63,64 . This and concurrent WIP1-mediated inactivation of p53…”

Section: Discussionmentioning

confidence: 99%

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

Milosevic

Fransson

Gulyás

et al. 2020

Preprint

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Majority 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.

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“…In the presence of inflammatory signals, neutrophils are activated quickly and migrate to inflammatory sites 21. Because of chronic inflammation, the persistent stimulus to neutrophils aggravates oxidative stress that damages the epithelium and induces pro-mutagenic DNA lesions 22.…”

Section: Discussionmentioning

confidence: 99%

<p>Dynamic impact of inﬂammation-based indices in colorectal cancer patients receiving FOLFOX-based chemotherapy</p>

Tao

Yuan

Pang

et al. 2019

CMAR

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Background: Inflammatory cellular response is implicated in the pathogenesis of colorectal cancer (CRC). Nevertheless, the dynamic effects of inflammatory index coNLR (neutrophil-to-lymphocyte ratio)-PLR (platelet-to-lymphocyte ratio) during chemotherapy remain elusive. Methods: The baseline clinical data and laboratory parameters of 480 CRC patients who received palliative resection of primary tumors and FOLFOX-based chemotherapy from January 2007 to January 2013 were retrospectively analyzed. Receiver operating characteristic curves were plotted to obtain the predictive NLR and PLR values, and to calculate the coNLR-PLR score. The Kaplan–Meier method was used to estimate the rates of recurrence-free survival (RFS) and overall survival (OS), and the Cox proportional hazards model was employed for analysis. Results: The dynamic cut-off values of NLR during four periods of chemotherapy were 3.029, 2.466, 2.102 and 1.795, respectively, and those of PLR were 216.438, 187.572, 169.027 and 174.368, respectively. A higher coNLR-PLR was significantly associated with lower rates of RFS and OS ( P <0.05). Both univariate and multivariate analyses showed that coNLR-PLR was a significant independent prognostic factor for RFS and OS ( P <0.05). Conclusions: CoNLR-PLR was a significant prognostic predictor for CRC patients who received FOLFOX-based chemotherapy. Evaluating this index can accurately predict the clinical treatment outcomes after chemotherapy.

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DNA damage-induced phosphatase Wip1 in regulation of hematopoiesis, immune system and inflammation

Cited by 40 publications

References 43 publications

WIP1 phosphatase as pharmacological target in cancer therapy

WIP1 phosphatase as pharmacological target in cancer therapy

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

<p>Dynamic impact of inﬂammation-based indices in colorectal cancer patients receiving FOLFOX-based chemotherapy</p>

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