Cleavage-mediated Activation of Chk1 during Apoptosis

Matsuura, Kenkyo; Wakasugi, Mitsuo; Yamashita, Katsumi; Matsunaga, Tsukasa

doi:10.1074/jbc.m803111200

Cited by 38 publications

(47 citation statements)

References 31 publications

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“…Chk1 inhibition hyperactivates ATM, ATR and caspase-2 after g-radiation and triggers a caspase-2-dependent apoptotic program that bypasses p53 deficiency and excess Bcl2 (Sidi et al, 2008). In addition, caspasemediated cleavage of Chk1 during apoptosis leads to enhanced apoptotic reactions (Okita et al, 2007;Matsuura et al, 2008). These data suggest a positive feedback role for Chk1 on apoptosis induction if cells encounter sufficient DNA damage to commit to apoptosis.…”

Section: Dna Damage Induced Apoptosis and Role Of Chk1mentioning

confidence: 91%

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

et al. 2010

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Section: Dna Damage Induced Apoptosis and Role Of Chk1mentioning

confidence: 91%

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

et al. 2010

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“…2C). Levels of CHK1 declined in Shef5 cells treated with cisplatin at later times, most likely as a consequence of caspase-mediated cleavage of this protein during apoptosis [34].…”

Section: Human Escs Fail To Activate Chk1 In Response To Dna Replicatmentioning

confidence: 99%

Human Embryonic Stem Cells Fail to Activate CHK1 and Commit to Apoptosis in Response to DNA Replication Stress

et al. 2012

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Pluripotent cells of the early embryo, to which embryonic stem cells (ESCs) correspond, give rise to all the somatic cells of the developing fetus. Any defects that occur in their genome or epigenome would have devastating consequences. Genetic and epigenetic change in human ESCs appear to be an inevitable consequence of long-term culture, driven by selection of variant cells that have a higher propensity for self-renewal rather than either differentiation or death. Mechanisms underlying the potentially separate events of mutation and subsequent selection of variants are poorly understood. Here, we show that human ESCs and their malignant counterpart, embryonal carcinoma (EC) cells, both fail to activate critical S-phase checkpoints when exposed to DNA replication inhibitors and commit to apoptosis instead. Human ESCs and EC cells also fail to form replication protein A, cH2AX, or RAD51 foci or load topoisomerase (DNA) II binding protein 1 onto chromatin in response to replication inhibitors. Furthermore, direct measurements of single-stranded DNA (ssDNA) show that these cells fail to generate the ssDNA regions in response to replication stress that are necessary for the activation of checkpoints and the initiation of homologous recombination repair to protect replication fork integrity and restart DNA replication. Taken together, our data suggest that pluripotent cells control genome integrity by the elimination of damaged cells through apoptosis rather than DNA repair, and therefore, mutations or epigenetic modifications resulting in an imbalance in cell death control could lead to genetic instability.

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“…The truncated CHK1 possesses much higher kinase activity, that is about 8-to 20-fold higher than its full-length counterpart (30). Ectopic expression of this super-active (SA)-CHK1 has been shown to induce apoptosis (30). Thus, these studies suggest that CHK1 is crucial for both cell-cycle and celldeath regulation.…”

Section: Introductionmentioning

confidence: 89%

“…In the case of caspase-dependent activation, caspase-mediated cleavage removes the C-terminal autoinhibitory domain of CHK1 and generates a truncated version composed of amino acids 1 to 299 (31). The truncated CHK1 possesses much higher kinase activity, that is about 8-to 20-fold higher than its full-length counterpart (30). Ectopic expression of this super-active (SA)-CHK1 has been shown to induce apoptosis (30).…”

Section: Introductionmentioning

confidence: 99%

“…For example, it is phosphorylated and activated by (i) ATM-and Rad3-related (ATR; ref. 23) and (ii) caspase-dependent cleavage when cells undergo apoptosis (30). In the case of caspase-dependent activation, caspase-mediated cleavage removes the C-terminal autoinhibitory domain of CHK1 and generates a truncated version composed of amino acids 1 to 299 (31).…”

Section: Introductionmentioning

confidence: 99%

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Mitotic Arrest by Tumor Suppressor RASSF1A Is Regulated via CHK1 Phosphorylation

Jiang

Rong

Sheikh

et al. 2014

Molecular Cancer Research

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The tumor suppressor RAS-association domain family 1 isoform A (RASSF1A) is known to play an important role in cell-cycle regulation. However, the molecular details about RASSF1A protein regulation are unclear. In this report, checkpoint kinase 1 (CHK1) is identified as a novel RASSF1A kinase that phosphorylates RASSF1A in vitro and under cellular conditions. Using tandem mass spectrometry and biochemical analysis, it was determined that CHK1 phosphorylates RASSF1A on Serine 184, which has been shown to be mutated in a subset of human primary nasopharyngeal carcinomas. Furthermore, Serine 184 phosphorylation of RASSF1A was significantly diminished by a CHK1-specific kinase inhibitor. Similarly, a kinase-dead CHK1 mutant was unable to phosphorylate Serine 184 whereas constitutively active-CHK1 enhanced phosphorylation. Molecular substitution of Serine 184 with aspartic acid, mimicking phosphorylation, abolished the ability of RASSF1A to interact with microtubules and induce M-phase arrest. Combined, these data indicate that phosphorylation of RASSF1A by CHK1 is important for mitotic regulation and provide valuable new insight into the regulatory mechanisms of RASSF1A function.Implications: This study reveals that CHK1-mediated phosphorylation of RASSF1A, at Serine 184, plays an important role in cell-cycle regulation and highlights that mutation of this CHK1 phosphorylation site in nasopharyngeal carcinoma has disease relevance.

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Cleavage-mediated Activation of Chk1 during Apoptosis

Cited by 38 publications

References 31 publications

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

Human Embryonic Stem Cells Fail to Activate CHK1 and Commit to Apoptosis in Response to DNA Replication Stress

Mitotic Arrest by Tumor Suppressor RASSF1A Is Regulated via CHK1 Phosphorylation

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