Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway

Chaturvedi, Priya; Eng, Wai K; Zhu, Yuan; Mattern, Michael R.; Mishra, Rubin; Hurle, Mark R.; Zhang, Xiaolong; Annan, Roland S.; Lu, Quinn; Faucette, Leo F.; Scott, Gregory J.; Li, Xiaotong; Carr, Steven A.; Johnson, Randall K.; Winkler, James D.; Zhou, Bin‐Bing S.

doi:10.1038/sj.onc.1202925

Cited by 377 publications

(303 citation statements)

References 37 publications

(48 reference statements)

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“…In keeping with a defect in the G2 delay, A-T cells do not exhibit a reduction in the activities of the Cdc2 kinase and the Cdc25C phosphatase, shortly after irradiation (Paules et al, 1995;Beamish et al, 1996;Blasina et al, 1999). Accordingly, the rapid modi®cation and activation of Chk2 in response to IR and other DSBs generating agents, but not to UV or HU, is also dependent on ATM (Matsuoka et al, 1998;Brown et al, 1999;Chaturvedi et al, 1999;Uziel, unpublished). The recent ®nding that Chk2 is an in vitro substrate of ATM (Rotman, unpublished) suggests this checkpoint kinase is directly targeted by ATM.…”

Section: G2/m Checkpointmentioning

confidence: 97%

“…Inactivation of Cdc25C is mediated by two protein kinases, Chk1 and Chk2 (HuCds1), which are phosphorylated and activated in response to DNA damage. Chk2 also responds to replication blocks such as those caused by treatment with hydroxyurea (HU) (Sanchez et al, 1997;Matsuoka et al, 1998;Blasina et al, 1999;Brown et al, 1999;Chaturvedi et al, 1999).…”

Section: G2/m Checkpointmentioning

confidence: 99%

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ATM: A mediator of multiple responses to genotoxic stress

1999

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The ATM protein kinase is the product of the gene responsible for the pleiotropic recessive disorder ataxiatelangiectasia. ATM-de®cient cells show enhanced sensitivity and greatly reduced responses to genotoxic agents that generate DNA double strand breaks (DSBs), such as ionizing radiation and radiomimetic chemicals, but exhibit normal responses to DNA adducts and base modi®cations induced by other agents. Therefore, DSBs are most likely the predominant signal for the activation of ATM-mediated pathways. Identi®cation of the ATM gene triggered extensive research aimed at elucidating the numerous functions of its large multifaceted protein product. While ATM has both nuclear and cytoplasmic functions, this review will focus on its roles in the nucleus where it plays a central role in the very early stages of damage detection and serves as a master controller of cellular responses to DSBs. By activating key regulators of multiple signal transduction pathways, ATM mediates the e cient induction of a signaling network responsible for repair of the damage, and for cellular recovery and survival.

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Section: G2/m Checkpointmentioning

confidence: 97%

Section: G2/m Checkpointmentioning

confidence: 99%

ATM: A mediator of multiple responses to genotoxic stress

1999

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“…It had been shown previously that phosphorylation of Chk2 on Thr68 is required for full activation of Chk2 via auto-(trans-or cis)phosphorylation. [9][10][11][12][13][31][32][33][34] We therefore investigated the role of Thr68-phosphorylation in the electrophoretic mobility shift of Chk2. We found that a Chk2 mutant, the alanine68 mutant (HA-Chk2 (T68A)), did not undergo the mobility shift when overexpressed (data not shown), indicating that Thr68 is required.…”

Section: Effect Of Wip1 On Thr68 Phosphorylation Of Chk2 Induced By Dmentioning

confidence: 99%

“…[9][10][11][12][13] Hence, we examined Thr68-phosphorylation and mobility shift of HA-Chk2 (WT) coexpressed with Flag-Wip1 (WT) or Flag-Wip1 (D314A) in 293T cells, before or after girradiation, by immunoblotting with antiphospho-Chk2 (Thr68). As shown in Figure 2b (upper panel), ectopic overexpression of HA-Chk2 per se induced some Thr68-autophosphorylation, but this phosphorylation, and that of the endogenous Chk2, was enhanced following g-irradiation, in cells not coexpressing Flag-Wip1 (WT).…”

Section: Effect Of Wip1 On Thr68 Phosphorylation Of Chk2 Induced By Dmentioning

confidence: 99%

“…[1][2][3][4][5][6][7][8] Upon DNA damage, Chk2 is activated by phosphorylation of threonine68 (Thr68) by ATM (ataxiatelangiectasia mutated). [9][10][11][12][13] Activated Chk2 then phosphorylates its downstream effectors, including the tumour suppressors p53, BRCA1, PML, E2F-1, and Cdc25 phosphatases, [14][15][16][17][18][19] thereby regulating cellular responses following DNA damage. Although the molecular basis of Chk2 kinase activation and roles of Chk2 in checkpoint activation are rather well understood, it remains largely unknown as to how activated Chk2 is inhibited to release from checkpoint arrest or to prevent cells from undergoing Chk2-mediated apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase

et al. 2005

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The antioncogenic Chk2 kinase plays a crucial role in DNA damage-induced cell-cycle checkpoint regulation. Here we show that Chk2 associates with the oncogenic protein Wip1 (wild-type p53-inducible phosphatase 1) (PPM1D), a p53-inducible protein phosphatase. Phosphorylation of Chk2 at threonine68 (Thr68), a critical event for Chk2 activation, which is normally induced by DNA damage or overexpression of Chk2, is inhibited by expression of wild-type (WT), but not a phosphatase-deficient mutant (D314A) of Wip1 in cultured cells. Furthermore, an in vitro phosphatase assay revealed that Wip1 (WT), but not Wip1 (D314A), dephosphorylates Thr68 on phosphorylated Chk2 in vitro, resulting in the inhibition of Chk2 kinase activity toward glutathione S-transferase-Cdc25C. Moreover, inhibition of Wip1 expression by RNA interference results in abnormally sustained Thr68 phosphorylation of Chk2 and increased susceptibility of cells in response to DNA damage, indicating that Wip1 acts as a negative regulator of Chk2 in response to DNA damage.

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Growing Yeast for Fun and Profit: Use of Saccharomyces Cerevisiae as a Model System in Drug Discovery

Ross‐Macdonald

2003

Model Organisms in Drug Discovery

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Yeast has great utility as a surrogate system to study aspects of mammalian biology. This utility extends to the drug discovery process, where yeast has been used to reveal the mechanism of action of compounds, to discover and characterize components of signaling pathways and to dissect protein function. These applications of yeast are illustrated by examples of research published by major pharmaceutical companies.

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Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway

Cited by 377 publications

References 37 publications

ATM: A mediator of multiple responses to genotoxic stress

ATM: A mediator of multiple responses to genotoxic stress

Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase

Growing Yeast for Fun and Profit: Use of Saccharomyces Cerevisiae as a Model System in Drug Discovery

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