Protein phosphatase PP4 is overexpressed in human breast and lung tumors

Wang, Bo; Zhao, Aishan; Sun, Lingling; Zhong, Xueyan; Zhong, Jianing; Wang, H.; Cai, Minhua; Li, Jing; Xu, Yi; Liao, Ji; Sang, Jianli; Chowdhury, Dipanjan; Pfeifer, Gerd P.; Yen, Yun; Xu, Xingzhi

doi:10.1038/cr.2008.274

Cited by 52 publications

(48 citation statements)

References 11 publications

(22 reference statements)

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“…Our results predict that the proposed clinical application of compounds that inhibit Wip1 will prove ineffective for tumors that retain a G1 checkpoint arrest after DNA damage and most effective for p53-proficient tumors that arrest primarily in G2 (40). endogenously tagged Cyclin B1-YFP Overexpression of Wip1 and PP4 occurs frequently in cancer and is associated with poor disease outcome (41)(42)(43). Because carcinogenesis requires multiple mutation events, overexpressed Wip1 or PP4 may help overcome the anticancer barrier posed by the DDR, promoting cell cycle progression after damage to the DNA and acquisition of additional mutations.…”

Section: Discussionmentioning

confidence: 99%

Distinct phosphatases antagonize the p53 response in different phases of the cell cycle

Shaltiël¹,

Aprelia²,

Saurin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The basic machinery that detects DNA damage is the same throughout the cell cycle. Here, we show, in contrast, that reversal of DNA damage responses (DDRs) and recovery are fundamentally different in G1 and G2 phases of the cell cycle. We find that distinct phosphatases are required to counteract the checkpoint response in G1 vs. G2. Whereas WT p53-induced phosphatase 1 (Wip1) promotes recovery in G2-arrested cells by antagonizing p53, it is dispensable for recovery from a G1 arrest. Instead, we identify phosphoprotein phosphatase 4 catalytic subunit (PP4) to be specifically required for cell cycle restart after DNA damage in G1. PP4 dephosphorylates Krüppel-associated box domain-associated protein 1-S473 to repress p53-dependent transcriptional activation of p21 when the DDR is silenced. Taken together, our results show that PP4 and Wip1 are differentially required to counteract the p53-dependent cell cycle arrest in G1 and G2, by antagonizing early or late p53-mediated responses, respectively. A cell's genomic integrity is constantly challenged by endogenous and exogenous sources of DNA damage. Doublestrand breaks (DSBs) are particularly threatening to the genomic stability of proliferative cells and provoke a checkpoint response that coordinates repair processes with further cell cycle progression to prevent the replication and segregation of broken DNA. This DNA damage response (DDR) is orchestrated by multiple kinases that sense the DNA damage and relay this signal (1). Cellular recovery from a DNA damage insult ultimately requires the termination of the DDR once repair of the DNA is complete.PI3-kinase-related kinases (PIKKs), ataxia telangiectasia mutated (ATM), and ATM-and Rad3-related (ATR) are activated by distinct structures of damaged DNA and phosphorylate histone H2AX in the vicinity of the damaged site to recruit repair proteins (2). In addition to such local events, ATM and ATR activate a subsequent layer of checkpoint kinase 2 (Chk2) and Chk1, respectively, that disseminates from the damaged site (3, 4). ATM also activates p38 mitogen-activated protein kinase (MAPK), which coordinates the DDR outside the nucleus (5, 6). Combined, these checkpoint kinases ensure that cell cycle progression is prevented at the G1/S or G2/M boundary (7).PIKKs and checkpoint kinases commonly converge on the transcription factor p53, a key regulator of stress responses. Phosphorylation of p53 prevents its degradation by mouse double minute 2 (Mdm2)-mediated polyubiquitination, allowing p53 to accumulate and induce its target genes, including p21 (1). Both p53 and its transcriptional target p21 are sufficient to impose an arrest in both G1 and G2, and they are absolutely required for a bona fide checkpoint arrest in G1 (8-11).Recovery from a checkpoint-induced arrest requires silencing of the checkpoint machinery and coincides with the removal of phosphorylations deposited by PIKKs and other checkpoint kinases. We have previously shown that WT p53-induced phosphatase 1 (Wip1) is essential for checkpoint recovery from a...

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Section: Discussionmentioning

confidence: 99%

Distinct phosphatases antagonize the p53 response in different phases of the cell cycle

Shaltiël¹,

Aprelia²,

Saurin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, PP4c levels are increased in human breast and lung tumours, and inhibition of PP4c expression increased the sensitivity of breast and lung cancer cells to cisplatin treatment, suggestive of an oncogenic function [25].…”

Section: Discussionmentioning

confidence: 99%

“…The additional observation that PP4c expression is elevated in breast cancer [25,26], further highlights the need for further studies to characterise its role in breast cells.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

The protein phosphatase 4 - PEA15 axis regulates the survival of breast cancer cells

Mohammed

Pickard

Mourtada-Maarabouni

2016

Cellular Signalling

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“…The PP4C-PP4R2 complex regulated the RPA2 phosphorylation level to regulate in turn the HR repair [93]. Overexpression of PP4 has been found in human breast tumors and lung tumors, and inhibition of its expression sensitizes cancer cells to cisplatin treatment [94]. Overexpression of PP4 and other protein phosphatases in tumors may confer resistance to chemotherapeutic drug-induced DNA damage because DNA damage-induced H2AX may be dephosphorylated regardless of repair.…”

Section: Pp4mentioning

confidence: 99%

Serine/threonine protein phosphatases in DNA damage response

Liu

2011

Chin. Sci. Bull.

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DNA damage response (DDR) is among the most important of the mechanisms that maintain genome stability which, when destabilized, predisposes organs to cancer. Reversible phosphorylation mediated by protein kinases and protein phosphatases regulates most, if not all, cellular activities, including DDR. Protein kinase inhibitors have become the main focus of targeted therapy and anticancer drug development. However, our limited knowledge of protein phosphatase function is compromising our capacity to develop therapeutic agents against phosphatases. In this review, we summarize the roles of serine/threonine protein phosphatases involved in DDR and propose that in situ dephosphorylation of phosphoproteins by protein phosphatases, instead of proteasome-mediated degradation of phosphoproteins, is mainly employed by cells. reversible protein phosphorylation, protein phosphatase, DNA damage, cancer Citation:Liu B, Xu X Z. Serine/threonine protein phosphatases in DNA damage response.

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Protein phosphatase PP4 is overexpressed in human breast and lung tumors

Cited by 52 publications

References 11 publications

Distinct phosphatases antagonize the p53 response in different phases of the cell cycle

Distinct phosphatases antagonize the p53 response in different phases of the cell cycle

The protein phosphatase 4 - PEA15 axis regulates the survival of breast cancer cells

Serine/threonine protein phosphatases in DNA damage response

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