An extra allele of Chk1 limits oncogene-induced replicative stress and promotes transformation

López-Contreras, Andrés J.; Gutierrez-Martinez, Paula; Specks, Julia; Rodrigo-Perez, Sara; Fernández-Capetillo, Óscar

doi:10.1084/jem.20112147

Cited by 100 publications

(64 citation statements)

References 31 publications

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“…It has been described that Chk1 may exert pro-tumorigenic functions by limiting the amount of cytotoxic DNA damage, allowing increased rates of proliferation. 17,25 Thus, the observed Fos-dependent Chk1 upregulation could contribute to the maintenance and progression of Fos-dependent OS.…”

Section: 24mentioning

confidence: 96%

“…S1). IF staining for γH2AX was performed in cells stably expressing Fos, and state-of-the-art high-throughput microscopy techniques were used to quantify the amount of RS 17 ( Fig. S1).…”

Section: Fos Expression In Fosmentioning

confidence: 99%

“…20 Furthermore, increased Chk1 levels facilitate transformation of Ras/E1a transduced cells by limiting oncogene-induced RS. 17 Interestingly, p53-deficient cells rely on Chk1 function during DNA damaging insults to enable cell survival, demonstrating a synthetic lethality with potential therapeutic relevance. 21 Finally, Chk1 tends to be overexpressed rather than lost in cancer, which would further support that increased Chk1 levels confer an advantage for tumor cells.…”

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confidence: 99%

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Fos-dependent induction of Chk1 protects osteoblasts from replication stress

et al. 2014

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Section: 24mentioning

confidence: 96%

“…S1). IF staining for γH2AX was performed in cells stably expressing Fos, and state-of-the-art high-throughput microscopy techniques were used to quantify the amount of RS 17 ( Fig. S1).…”

Section: Fos Expression In Fosmentioning

confidence: 99%

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confidence: 99%

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Fos-dependent induction of Chk1 protects osteoblasts from replication stress

et al. 2014

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“…Therefore, it is possible that despite the high expression of pCHK1 Ser345 , pCDC25C Ser216 can still activate CDK1/Cyclin B1 complex and trigger G2/M transition. High levels of pCHK1 Ser345 in the cancer cells might function as a compensatory DNA repair mechanism helping tumor cells to cope with increased levels of DNA damage and replicative stress 34. However, we cannot exclude that despite the pCHK1 Ser345 activation, the downstream targets are not activated and functional which could lead to bypass of G2 arrest.…”

Section: Discussionmentioning

confidence: 94%

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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“…In this context, tumours need to maintain a proficient RS-response to cope with the high levels of RS that are induced by oncogenes and ensure their survival. In support for these ideas, a mild increase of Chk1 levels facilitates transformation with Ras and E1A by reducing the amount of RS-induced by the oncogenes and thus limiting the toxicity of the transformation process [78]. In this context, we believe that oncogenes that promote DNA replication, such as E2F or Myc, will upregulate factors that are necessary to cope with the increased replication rates (RS-buffers) as part of their transcriptional response.…”

Section: Rs As a Brake For Tumorigenesismentioning

confidence: 89%

Replication stress and cancer: It takes two to tango

Lecona

Fernández-Capetillo

2014

Experimental Cell Research

119

107

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Problems arising during DNA replication require the activation of the ATR-CHK1 pathway to ensure the stabilization and repair of the forks, and to prevent the entry into mitosis with unreplicated genomes. Whereas the pathway is essential at the cellular level, limiting its activity is particularly detrimental for some cancer cells. Here we review the links between replication stress (RS) and cancer, which provide a rationale for the use of ATR and Chk1 inhibitors in chemotherapy. First, we describe how the activation of oncogene-induced RS promotes genome rearrangements and chromosome instability, both of which could potentially fuel carcinogenesis. Next, we review the various pathways that contribute to the suppression of RS, and how mutations in these components lead to increased cancer incidence and/or accelerated ageing. Finally, we summarize the evidence showing that tumours with high levels of RS are dependent on a proficient RS-response, and therefore vulnerable to ATR or Chk1 inhibitors.

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An extra allele of Chk1 limits oncogene-induced replicative stress and promotes transformation

Abstract: Protection from replicative stress conferred by Chk1 promotes transformation.

Cited by 100 publications

References 31 publications

Fos-dependent induction of Chk1 protects osteoblasts from replication stress

Fos-dependent induction of Chk1 protects osteoblasts from replication stress

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

Replication stress and cancer: It takes two to tango

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