Role of Human Cds1 (Chk2) Kinase in DNA Damage Checkpoint and Its Regulation by p53

Tominaga, Kaoru; Morisaki, Hirobumi; Kaneko, Yoko; Fujimoto, Atsushi; Tanaka, Takashi; Ohtsubo, Motoaki; Hirai, Momoki; Okayama, Hiroto; Ikeda, Kyoji; Nakanishi, Makoto

doi:10.1074/jbc.274.44.31463

Cited by 87 publications

(85 citation statements)

References 44 publications

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“…While many studies have investigated how CHK2 activates and stabilizes p53 [6,17,[27][28][29], the possible role of p53 in regulating CHK2 protein level or activity has not been well studied. Studies conducted in tumor cell lines and tissue specimens have previously demonstrated an inverse correlation between p53 and CHK2 expression [30,31]. However, in our previous and current studies, neither HCT116, HCT116 p53−/− nor p53 wild-type and mutant ovarian cancer cell lines demonstrated a dramatic inverse correlation of p53 and CHK2 protein levels after irofulven treatment [42].…”

Section: Discussioncontrasting

confidence: 67%

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Irofulven induces replication-dependent CHK2 activation related to p53 status

Wang

Wiltshire

Senft

et al. 2007

Biochemical Pharmacology

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CHK2 and p53 are frequently mutated in human cancers. CHK2 is known to phosphorylate and stabilize p53. CHK2 has also been implicated in DNA repair and apoptosis induction. However, whether p53 affects CHK2 activation and whether CHK2 activation modulates chemosensitivity are unclear. In this study, we found that in response to the DNA damage agent, irofulven, CHK2 activation, rather than its expression, is inversely correlated to p53 status. Irofulven inhibits DNA replication and induces chromosome aberrations (breaks and radials) and p53-dependent cell cycle arrest. Pretreatment of cells with the DNA polymerase inhibitor, aphidicolin, resulted in reduction of irofulven-induced CHK2 activation and foci formation, indicating that CHK2 activation by irofulven is replication-dependent. Furthermore, by using ovarian cancer cell lines expressing dominant-negative CHK2 and CHK2-knockout HCT116 cells, we found that CHK2 activation contributes to the control of S and G2/M cell cycle arrests, but not chemosensitivity to irofulven. Overall, this study demonstrates that in response to irofulven-induced DNA damage, the activation of CHK2 is dependent on DNA replication and related to p53 status. By controlling cell cycle arrest and DNA replication, p53 affects CHK2 activation. CHK2 activation contributes to cell cycle arrest, but not chemosensitivity.

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Section: Discussioncontrasting

confidence: 67%

“…An inverse correlation between p53 and CHK2 expression has been reported in tumor cell lines and tissue specimens [30,31]. A recent report suggested that p53 negatively regulates CHK2 expression by modulating the function of transcription factor NF-Y [32].…”

Section: Introductionmentioning

confidence: 95%

Irofulven induces replication-dependent CHK2 activation related to p53 status

Wang

Wiltshire

Senft

et al. 2007

Biochemical Pharmacology

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“…Functional proteins downstream from the p53 interactive signaling pathways, such as ataxia telangiectasia mutated (ATM) and homolog of ATM (ATR), are central to the DNA damage response (Zhou and Elledge, 2000;Goodarzi et al, 2003;Dodson et al, 2004;Irarrazabal et al, 2004;Kastan, 2004;Yang et al, 2004). Further downstream targets (substrates) of ATM/ATR include the checkpoint protein kinases Chk1 and Chk2 (Ma et al, 1998;Matsuoka et al, 1998;Sanchez et al, 1999;Tominaga et al, 1999). Chk1 and Chk2 are thought to mediate different types of DNA damage to the specific cellular responses.…”

Section: Role Of P53 In Uv Irradiation-induced Dna Damagementioning

confidence: 99%

Stress-induced corneal epithelial apoptosis mediated by K+ channel activation

2006

Progress in Retinal and Eye Research

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One of the functional roles of the corneal epithelial layer is to protect the cornea, lens and other underlying ocular structures from damages caused by environmental insults. It is important for corneal epithelial cells to maintain this function by undergoing continuous renewal through a dynamic process of wound healing. Previous studies in corneal epithelial cells have provided substantial evidence showing that environmental insults, such as ultraviolet (UV) irradiation and other biohazards, can induce stress-related cellular responses resulting in apoptosis and thus interrupt the dynamic process of wound healing. We found that UV irradiation-induced apoptotic effects in corneal epithelial cells are started by the hyperactivation of K + channels in the cell membrane resulting in a fast loss of intracellular K + ions. Recent studies provide further evidence indicating that these complex responses in corneal epithelial cells are resulted from the activation of stressrelated signaling pathways mediated by K + channel activity. The effect of UV irradiation on corneal epithelial cell fate shares common signaling mechanisms involving the activation of intracellular responses that are often activated by the stimulation of various cytokines. One piece of evidence for making this distinction is that at early times UV irradiation activates a Kv3.4 channel in corneal epithelial cells to elicit activation of c-Jun N-terminal kinase cascades and p53 activation leading to cell cycle arrest and apoptosis. The hypothetic model is that UV-induced potassium channel hyperactivity as an early event initiates fast cell shrinkages due to the loss of intracellular potassium, resulting in the activation of scaffolding protein kinases and cytoskeleton reorganizations. This review article presents important control mechanisms that determine Kv channel activity-mediated cellular responses in corneal epithelial cells, involving activation of stress-induced signaling pathways, arrests of cell cycle progression and/or induction of apoptosis.

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“…Activated either through phosphorylation by the upstream kinase Ataxia Telangiectasia Mutated (ATM) (Matsuoka et al, 1998) or independently of ATM (Theard et al, 2001), CHK2 undergoes oligomerization and auto-phosphorylation (Lee and Chung, 2001;Ahn et al, 2002;Xu et al, 2002). Thereafter, CHK2 spreads the damage signal by phosphorylating multiple substrates including the Cdc25A (Falck et al, 2001b) and Cdc25C (Matsuoka et al, 1998) phosphatases, BRCA1 (Lee et al, 2000), and p53 (Tominaga et al, 1999;Caspari, 2000), thereby triggering different pathways involved in growth arrest or apoptosis .…”

Section: Introductionmentioning

confidence: 99%

Alternative splicing and mutation status of CHEK2 in stage III breast cancer

et al. 2004

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The DNA damage checkpoint kinase, CHK2, promotes growth arrest or apoptosis through phosphorylating targets such as Cdc25A, Cdc25C, BRCA1, and p53. Both germline and somatic loss-of-function CHEK2 mutations occur in human tumours, the former linked to the LiFraumeni syndrome, and the latter found in diverse types of sporadic malignancies. Here we examined the status of CHK2 by genetic and immunohistochemical analyses in 53 breast carcinomas previously characterized for TP53 status. We identified two CHEK2 mutants, 470T4C (Ile157Thr), and a novel mutation, 1368insA leading to a premature stop codon in exon 13. The truncated protein encoded by CHEK2 carrying the 1368insA was stable yet mislocalized to the cytoplasm in tumour sections and when ectopically expressed in cultured cells. Unexpectedly, we found CHEK2 to be subject to extensive alternative splicing, with some 90 splice variants detected in our tumour series. While all cancers expressed normal-length CHEK2 mRNA together with the spliced transcripts, we demonstrate and/or predict some of these splice variants to lack CHK2 function and/or localize aberrantly. We conclude that cytoplasmic sequestration may represent a novel mechanism to disable CHK2, and propose to further explore the significance of the complex splicing patterns of this tumour suppressor gene in oncogenesis.

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Role of Human Cds1 (Chk2) Kinase in DNA Damage Checkpoint and Its Regulation by p53

Cited by 87 publications

References 44 publications

Irofulven induces replication-dependent CHK2 activation related to p53 status

Irofulven induces replication-dependent CHK2 activation related to p53 status

Stress-induced corneal epithelial apoptosis mediated by K+ channel activation

Alternative splicing and mutation status of CHEK2 in stage III breast cancer

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