Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions

Gorgoulis, Vassilis G.; Vassiliou, Leandros-Vassilios; Karakaidos, Panagiotis; Zacharatos, Panayotis; Kotsinas, Athanassios; Liloglou, Triantafillos; Venere, Monica; DiTullio, Richard A.; Kastrinakis, Nikolaos G.; Levy, Brynn; Kletsas, Dimitris; Yoneta, Akihiro; Herlyn, Meenhard; Kittas, Christos; Halazonetis, Thanos D.

doi:10.1038/nature03485

Cited by 1,875 publications

(1,932 citation statements)

References 27 publications

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“…The possible existence of an ATM-dependent surveillance system for Bcl-2 in breast cancer development is consistent with recent findings showing that activation of ATM is an early event in lung and bladder cancer initiation, and that attenuation of ATM function promotes the cancer progression (Bartkova et al, 2005;Gorgoulis et al, 2005). The proposed mechanism for ATM activation in lung and bladder tumorigenesis is DNA replication stress imposed by abnormal cell cycle progression, which produces DNA damage and therefore activation of ATM.…”

Section: Bcl-2 Activates Atm In Mcf-7 Cellssupporting

confidence: 88%

“…Ataxia telangiectasia mutated protein signaling contributes to oncogenemediated activation of p14 ARF -p53 (Li et al, 2004). Oncogene-driven abnormal cell-cycle progression was found to activate ATM in precancerous lesions of the lung and bladder and attenuation of this ATM surveillance system facilitates cancer development (Bartkova et al, 2005;Gorgoulis et al, 2005). In breast cancer, phosporylation of Chk2 at the ATM phosphorylation site, Thr68, was detected in the absence of irradiation (DiTullio et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Identification of an ataxia telangiectasia-mutated protein mediated surveillance system to regulate Bcl-2 overexpression

et al. 2006

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Bcl-2 can both promote and attenuate tumorigenesis. Although the former function is relatively well characterized, the mechanism of the latter remains elusive. We report here that enforced Bcl-2 expression in MCF7 cells stabilizes p53, induces phosphorylation of p53 serine 15 (p53pSer15) and inhibits MCF7 cell growth. Consistent with p53 Ser15 being a target of ataxia telangiectasia mutated protein(ATM)/ATR (ATM-and rad3-related) in the DNA damage response, Bcl-2 activates ATM by inducing ATM Ser1981 phosphorylation, which is accompanied with the phosphorylaton of two additional ATM substrates, Chk2 Thr68 and H2AX Ser139. Downregulation of ATM using a specific small interference RNA fragment (ATMRNAi) abolished Bcl-2-induced p53pSer15 and Bcl-2-mediated growth inhibition of MCF7 cells. Ectopic expression of a dominant-negative p53 mutant, p53175H, partially rescued this growth inhibition. Taken together, these observations demonstrate the contribution of ATM-p53 function to Bcl-2-mediated inhibition of MCF7 cell growth, indicating an ATM-mediated surveillance system for regulating Bcl-2 overexpression. Consistent with this concept, we found that MCF7 cells express Bcl-2 heterogeneously with 34.5% of cells being Bcl-2 negative. In general, Bcl-2-positive MCF7 cells proliferate slower than those of Bcl-2 negative. Thus, we provide evidence suggesting that activation of ATM suppresses Bcl-2-induced tumorigenesis, and that attenuation of ATM function may be an important event in breast cancer progression.

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Section: Bcl-2 Activates Atm In Mcf-7 Cellssupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Identification of an ataxia telangiectasia-mutated protein mediated surveillance system to regulate Bcl-2 overexpression

et al. 2006

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“…MECs within CERM D1À/À TEBs expressed markers of an activated DNA damage response The occurrence of a DNA damage response can be ascertained by immunohistochemical detection of wellcharacterized antibodies such as serine 139-phosphorylated histone H2AX (gH2AX), threonine 68-phosphorylated Chk2 (pT-Chk2) and serine 15-phosphorylated p53 (pS-p53) (Bartkova et al, 2005;Gorgoulis et al, 2005). The mean percentage of MECs within TEBs demonstrating nuclear-localized gH2AX was significantly higher in CERM D1À/À (8.3%±1.0) compared to CERM glands (0.97%±0.27) (P ¼ 0.001, MannWhitney test; Figures 5a-c).…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies showed that cyclin E overexpression causes DNA damage and checkpoint activation (Spruck et al, 1999;Ekholm-Reed et al, 2004;Bartkova et al, 2005;Minella et al, 2007). Aberrant stimulation of cell proliferation leads to DNA replication stress, doublestrand breaks, genomic instability, activation of DNA damage checkpoints and p53-dependent apoptosis or cell cycle arrest to ensure genomic integrity (Gorgoulis et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Loss of cyclin D1 in concert with deregulated estrogen receptor α expression induces DNA damage response activation and interrupts mammary gland morphogenesis

et al. 2007

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We have previously shown that increased and deregulated estrogen receptor a expression in the mammary gland leads to the development of proliferative disease and cancer. To address the importance of cyclin D1 in ERa-mediated mammary tumorigenesis, we crossed ERa-overexpressing mice with cyclin D1 knockout mice. Mammary gland morphogenesis was completely interrupted in the ERa-overexpressing cyclin D1-deficient triple transgenic mice. In addition to a highly significant reduction in mammary epithelial cell proliferation, cyclin E was upregulated resulting in DNA damage checkpoint activation and apoptosis. This imbalance between proliferative and apoptotic rates in conjunction with remarkable structural defects and cellular disorganization in the terminal end buds interrupted ductal morphogenesis. Interestingly, the structure of the mammary fat pad was fundamentally altered by the consequences of overexpressing ERa in the epithelial cells in the absence of cyclin D1 illustrating how alterations in the epithelial compartment can impact surrounding stromal composition. Transplantation of embryonic ERa-overexpressing and cyclin D1-deficient mammary epithelium into the cleared fat pad of wild-type mice did not rescue the aberrant mammary gland phenotype indicating that it was intrinsic to the mammary epithelial cells. In conclusion, although cyclin D1 is not essential for proliferation of normal mammary epithelial cells, ERa-overexpressing cells are absolutely dependent on cyclin D1 for proliferation. This differential requirement for cyclin D1 in normal vs abnormal mammary epithelial cells supports the application of cyclin D1 inhibitors as therapeutic interventions in ERa-overexpressing breast cancers.

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“…It is envisaged that centromeric regions intrinsically present replication barriers due to the condensed structure of heterochromatin, and unresolved replication barriers and/or asynchronous replication may result in DNA damage such as DNA double-strand breaks (Leach et al, 2000). Overstimulation of cell proliferation pathways has been shown to generate replication stress and DNA double-strand breaks at regions difficult to replicate, due to the conflict between unscheduled DNA synthesis and uncoordinated prereplicative complex assembly (Bartkova et al, 2005;Gorgoulis et al, 2005). Indeed, p16 INK4a deletion, which promotes cell proliferation, is detected in both of our telomerase-immortalized cell lines (Li et al, 2006;Cheung et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Impact of G2 checkpoint defect on centromeric instability

et al. 2010

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Centromeric instability is characterized by dynamic formation of centromeric breaks, deletions, isochromosomes and translocations, which are commonly observed in cancer. So far, however, the mechanisms of centromeric instability in cancer cells are still poorly understood. In this study, we tested the hypothesis that G 2 checkpoint defect promotes centromeric instability. Our observations from multiple approaches consistently support this hypothesis. We found that overexpression of cyclin B1, one of the pivotal genes driving G 2 to M phase transition, impaired G 2 checkpoint and promoted the formation of centromeric aberrations in telomerase-immortalized cell lines. Conversely, centromeric instability in cancer cells was ameliorated through reinforcement of G 2 checkpoint by cyclin B1 knockdown. Remarkably, treatment with KU55933 for only 2.5 h, which abrogated G 2 checkpoint, was sufficient to produce centromeric aberrations. Moreover, centromeric aberrations constituted the major form of structural abnormalities in G 2 checkpoint-defective ataxia telangiectasia cells. Statistical analysis showed that the frequencies of centromeric aberrations in G 2 checkpoint-defective cells were always significantly overrepresented compared with random assumption. As there are multiple pathways leading to G 2 checkpoint defect, our finding offers a broad explanation for the common occurrence of centromeric aberrations in cancer cells.

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Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions

Cited by 1,875 publications

References 27 publications

Identification of an ataxia telangiectasia-mutated protein mediated surveillance system to regulate Bcl-2 overexpression

Identification of an ataxia telangiectasia-mutated protein mediated surveillance system to regulate Bcl-2 overexpression

Loss of cyclin D1 in concert with deregulated estrogen receptor α expression induces DNA damage response activation and interrupts mammary gland morphogenesis

Impact of G2 checkpoint defect on centromeric instability

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