Coupling Cellular Localization and Function of Checkpoint Kinase 1 (Chk1) in Checkpoints and Cell Viability

Wang, Jingna; Han, Xiangzi; Feng, Xiujing; Wang, Benlian; Zhang, Youwei

doi:10.1074/jbc.m112.350397

Cited by 34 publications

(49 citation statements)

References 29 publications

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“…S6A). This observation is in conflict with the observations made by other groups, for example, Wang et al (31), with ectopically expressed CHK1 that showed persistent nuclear localization. We speculate that the discrepancy may result from the difference between endogenous CHK1 and ectopically expressed protein and also in the level of expression for the latter, as we also observed in HA-CHK1-transfected cells that cells expressing higher levels of CHK1 tend to retain the protein in the nucleus.…”

Section: Cdt2contrasting

confidence: 94%

Candidate tumor suppressor BTG3 maintains genomic stability by promoting Lys63-linked ubiquitination and activation of the checkpoint kinase CHK1

Cheng

Lin

Shieh

2013

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

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B-cell translocation gene 3 (BTG3) is a member of the antiproliferative BTG/ Transducer of ErbB2 gene family and is induced by genotoxic stress in a p53-and Checkpoint kinase 1 (CHK1)-dependent manner. Down-regulation of BTG3 has been observed in human cancers, suggesting that it plays an important role in tumor suppression, although the underlying mechanisms are unclear. Here, we report that BTG3 interacts with CHK1, a key effector kinase in the cell cycle checkpoint response, and regulates its phosphorylation and activation. Upon interaction, BTG3 mediates K63-linked ubiquitination of CHK1 at Lys132 through the cullin-RING ligase 4Cdt2 E3 complex, thus facilitating CHK1 chromatin association. We show that BTG3-depleted cells phenocopy those CHK1-deficient cells, exhibiting increased cell death after replication block and impaired chromosome alignment and segregation. These defects could be corrected by wild-type BTG3 but not by a mutant impaired in CHK1 interaction. We propose that BTG3-dependent CHK1 ubiquitination contributes to its chromatin localization and activation and that a defect in this regulation may increase genome instability and promote tumorigenesis.

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Section: Cdt2contrasting

confidence: 94%

Candidate tumor suppressor BTG3 maintains genomic stability by promoting Lys63-linked ubiquitination and activation of the checkpoint kinase CHK1

Cheng

Lin

Shieh

2013

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

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“…Previous studies have suggested that even though the cytoplasmic pool of CHK1 is important for checkpoint function, it is the nuclear pool of CHK1 that supports cell viability,36 which does not directly support our observations in VSCC. However, few reports have implicated CHK1 in apoptosis via CHK1‐mediated phosphorylation of p73 at Ser47, resulting in a strong increase in p73 transcription activity in response to DNA damage 37.…”

Section: Discussioncontrasting

confidence: 99%

Evaluation of CHK1 activation in vulvar squamous cell carcinoma and its potential as a therapeutic target in vitro

et al. 2018

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CHK1 is an important regulator of the cell cycle and DNA damage response, and its altered expression has been identified in various tumors. Chk1 inhibitors are currently being evaluated as monotherapy and as potentiators of chemotherapy in clinical settings. However, to our knowledge, no previous study has investigated either the activation status or the therapeutic potential of CHK1 targeting in vulvar cancer. Therefore, we examined the expression status of activated CHK1 forms pCHK1Ser345, pCHK1Ser317, pCHK1Ser296, and pCHK1Ser280 in 294 vulvar squamous cell carcinomas (VSCC) using immunohistochemistry and analyzed their relationships with various clinicopathological variables and clinical outcome. To aid translation of preclinical studies, we also assessed cell sensitivity to the Chk1 inhibition in two vulvar cancer cell lines. Compared to the levels of pCHK1Ser345, pCHK1Ser317, pCHK1Ser296, and pCHK1Ser280 in normal vulvar squamous epithelium, high nuclear pCHK1Ser345 expression was found in 57% of vulvar carcinomas, whereas low nuclear pCHK1Ser317, pCHK1Ser296, and pCHK1Ser280 expressions were observed in 58%, 64%, and 40% of the cases, respectively. Low levels of pCHK1Ser317 and pCHK1Ser280 in the nucleus correlated significantly with advanced tumor behaviors and aggressive features. None of pCHK1Ser345, pCHK1Ser317, pCHK1Ser296, and pCHK1Ser280 forms were identified as prognostic factors. In vitro inhibition of CHK1 by small molecular inhibitors or siRNA reduced viability by inducing DNA damage and apoptosis of vulvar cancer cell lines. In summary, we conclude that cellular functions regulated by CHK1 are phosphorylation/localization‐dependent and deregulation of CHK1 function occurs in VSCC and might contribute to tumorigenesis. Targeting CHK1 might represent as a useful antitumor strategy for the subgroup of VSCC harboring p53 mutations.

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“…43 Recent mouse work supports an impact of Mcph1 deficiency on centrosomal Chk1, suggesting that pericentrin may affect Chk1 at the centrosome. 36 If the key controls on Chk1 depend on its activation through a nuclear-cytosolic/centrosomal feedback loop, 44 localization of even a small fraction of Chk1 within the PCM may be a mechanism by which Mcph1 and pericentrin determine its interactions with its regulators.…”

Section: Discussionmentioning

confidence: 99%

Promoter hijack reveals pericentrin functions in mitosis and the DNA damage response

et al. 2013

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Coupling Cellular Localization and Function of Checkpoint Kinase 1 (Chk1) in Checkpoints and Cell Viability

Cited by 34 publications

References 29 publications

Candidate tumor suppressor BTG3 maintains genomic stability by promoting Lys63-linked ubiquitination and activation of the checkpoint kinase CHK1

Candidate tumor suppressor BTG3 maintains genomic stability by promoting Lys63-linked ubiquitination and activation of the checkpoint kinase CHK1

Evaluation of CHK1 activation in vulvar squamous cell carcinoma and its potential as a therapeutic target in vitro

Promoter hijack reveals pericentrin functions in mitosis and the DNA damage response

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