Cell-cycle checkpoints and cancer

Kastan, Michael B.; Bártek, Jiří

doi:10.1038/nature03097

Cited by 2,480 publications

(2,207 citation statements)

References 93 publications

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“…Moreover, constitutive activation of ATM and CHK2 has recently been demonstrated in a subset of malignant tumours (Bartkova et al, 2005). It is therefore tempting to speculate that the activation status of ATM and CHK2 may significantly interfere with the radiosensitivity and/or chemosensitivity of tumour cells (Kastan and Bartek, 2004). However, this hypothesis has not yet been tested clinically in patients with oesophageal cancer.…”

Section: Discussionmentioning

confidence: 99%

The predictive value of molecular markers (p53, EGFR, ATM, CHK2) in multimodally treated squamous cell carcinoma of the oesophagus

et al. 2007

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Pretherapeutic identification of oesophageal squamous cell carcinomas that will respond to neoadjuvant chemoradiotherapy is an important attempt for improvement of patient's prognosis. In the current study, pretherapeutic biopsies from 94 oesophageal squamous cell carcinomas (cT3, cN0/ þ , cM0) in patients who underwent neoadjuvant chemoradiotherapy (RCTx: 45 Gy plus cisplatin and 5-fluorouracil) and subsequent oesophagectomy in the setting of a single-centre prospective treatment trial were investigated by means of immunohistochemistry. Expression of proteins involved in DNA repair and/or cell-cycle regulation, that is p53, p53 (phosphorylated at Ser15), EGFR, ATM protein kinase (phosphorylated at Ser1981) and checkpoint kinase 2 (CHK2) (phosphorylated at Thr68) was correlated with the response to RCTx and with overall survival. Tumours that were positive for CHK2 expression more frequently showed clinically determined regression after RCTx (69.4%) than tumours that were negative for CHK2 expression (32.1%; P ¼ 0.0011), whereas other parameters did not correlate with tumour regression. Expression of ATM correlated with expression of CHK2 (P ¼ 0.0061) and p53-phospho (P ¼ 0.0064). Expression of p53 correlated with expression of p53-phospho (Po0.0001). In contrast to clinical and histopathological response evaluation, none of the molecular parameters under investigation correlated with overall survival. In conclusion, expression analysis of p53, EGFR CHK2 and ATM has no predictive value in multimodally treated oesophageal squamous cell carcinoma.

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Section: Discussionmentioning

confidence: 99%

The predictive value of molecular markers (p53, EGFR, ATM, CHK2) in multimodally treated squamous cell carcinoma of the oesophagus

et al. 2007

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“…The G 2 arrest represents a mechanism by which many cell types, including those of epithelial origin, are able to halt DNA segregation and thereby prevent an accumulation of mutations, which would otherwise promote carcinogenesis (Kastan and Bartek, 2004). This arrest serves to allow time for repair of DNA damage, which may then result in resumption of proliferation or, if the damage is too severe, permanent arrest (Linke et al, 1996) or senescence (Narita et al, 2003) to prevent further genetic instability (Almasan et al, 1995a;Bindra and Glazer, 2005;.…”

Section: Discussionmentioning

confidence: 99%

“…The checkpoint pathway implicates the DNA damage sensors, ataxia telangiectasia mutated/ataxia telangiectasia mutated and Rad3 related (ATM/ATR) and effectors, Cell Cycle Checkpoint Kinase 1/Cell Cycle Checkpoint Kinase 2 (CHK1/CHK2), which converge on the regulation of the CDC25C phosphatase and its downstream target, cyclin-dependent kinase 1 (CDK1) (Kastan and Bartek, 2004). In wild-type p53 cells, both a G 1 and G 2 arrest occur in response to DNA damage (Wahl and Carr, 2001).…”

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confidence: 99%

E2F4 regulates a stable G2 arrest response to genotoxic stress in prostate carcinoma

et al. 2006

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The retinoblastoma (pRB) family proteins regulate the E2F transcription factors; their complexes regulate critical transitions through the cell cycle. The function of these pRB family/E2F complexes, which includes p130/ E2F4, in response to genotoxic agents, is not well understood. We investigated the role of E2F4 in the genotoxic stress response. Following radiation treatment, E2F4 colocalized with p130 in the nucleus during a radiation-induced stable G 2 -phase arrest. Arrested cells had significantly decreased expression of Cyclins A2 and B1 and decreased phosphorylation of mitotic protein monoclonal-2 (MPM-2) mitotic proteins. Small interference RNA (siRNA)-mediated knockdown of E2F4 sensitized cells to subsequent irradiation, resulting in enhanced cellular DNA damage and cell death, as determined by caspase activation and decreased clonogenic cell survival. Downstream E2F4 targets potentially involved in the progression from G 2 into M phase were identified by oligonucleotide microarray expression profiling. Chromatin immunoprecipitation localized E2F4 at promoter regions of the Bub3 and Pttg1 mitotic genes following irradiation, which were among the downregulated genes identified by the microarray. These data suggest that in response to radiation, E2F4 becomes active in the nucleus, enforces a stable G 2 arrest by target gene repression, and thus provides increased cell survival ability by minimizing propagation of cells that have irreparable DNA damage.

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“…Chk2 in turn inhibits the Cdc25 phosphatase, a central activator of the main cell‐cycle regulators Cdk1 and Cdk2 in animals. In addition, the ATM pathway activates Wee1, a negative regulator of Cdk1 and Cdk2 providing a parallel block of the cell cycle (Kastan & Bartek, 2004; Harper & Elledge, 2007; Yata & Esashi, 2009). …”

Section: Introductionmentioning

confidence: 99%

The plant‐specific CDKB 1‐ CYCB 1 complex mediates homologous recombination repair in Arabidopsis

et al. 2016

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Upon DNA damage, cyclin‐dependent kinases (CDKs) are typically inhibited to block cell division. In many organisms, however, it has been found that CDK activity is required for DNA repair, especially for homology‐dependent repair (HR), resulting in the conundrum how mitotic arrest and repair can be reconciled. Here, we show that Arabidopsis thaliana solves this dilemma by a division of labor strategy. We identify the plant‐specific B1‐type CDKs (CDKB1s) and the class of B1‐type cyclins (CYCB1s) as major regulators of HR in plants. We find that RADIATION SENSITIVE 51 (RAD51), a core mediator of HR, is a substrate of CDKB1‐CYCB1 complexes. Conversely, mutants in CDKB1 and CYCB1 fail to recruit RAD51 to damaged DNA. CYCB1;1 is specifically activated after DNA damage and we show that this activation is directly controlled by SUPPRESSOR OF GAMMA RESPONSE 1 (SOG1), a transcription factor that acts similarly to p53 in animals. Thus, while the major mitotic cell‐cycle activity is blocked after DNA damage, CDKB1‐CYCB1 complexes are specifically activated to mediate HR.

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Cell-cycle checkpoints and cancer

Cited by 2,480 publications

References 93 publications

The predictive value of molecular markers (p53, EGFR, ATM, CHK2) in multimodally treated squamous cell carcinoma of the oesophagus

The predictive value of molecular markers (p53, EGFR, ATM, CHK2) in multimodally treated squamous cell carcinoma of the oesophagus

E2F4 regulates a stable G2 arrest response to genotoxic stress in prostate carcinoma

The plant‐specific CDKB 1‐ CYCB 1 complex mediates homologous recombination repair in Arabidopsis

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