Abstract
BackgroundCHK2 kinase is a tumor suppressor that plays important role in DNA damage signaling, cell cycle regulation and DNA damage induced apoptosis. CHK2 kinase expression was known to be ubiquitous in mammalian cells. CHK2-/- cells were remarkably resistant to DNA damage induced apoptosis, mimicking the clinical behavior of non-small cell lung cancer to conventional chemo and radiation therapy.ResultWe reported that the CHK2 expression is diminished or absent in both non-small cell lung cancer (NSCLC) cell lines and clinical lung cancer tumor specimens. The absent CHK2 expression in NSCLC was due to hypermethylation of the CHK2 gene promoter, preventing from binding of a transcriptional factor, leading to silence of the CHK2 gene transcription.ConclusionSince the CHK2 null mice showed a remarkable radioresistance, which bear significant similarity to clinical behavior of NSCLC, down-regulation of CHK2 kinase expression by CHK2 gene silencing and methylation in non-small cell lung cancer suggest a critical role of CHK2 kinase in DNA damage induced apoptosis and a novel mechanism of the resistance of NSCLC to DNA damage based therapy.
Highlights
CHK2 kinase is an important cell cycle regulator in DNA damage response pathway
Since the CHK2 null mice showed a remarkable radioresistance, which bear significant similarity to clinical behavior of NSCLC, down-regulation of CHK2 kinase expression by CHK2 gene silencing and methylation in non-small cell lung cancer suggest a critical role of CHK2 kinase in DNA damage induced apoptosis and a novel mechanism of the resistance of NSCLC to DNA damage based therapy
In response to exogenous or endogenous DNA damage agents, CHK2 is phosphorylated and activated by ATM kinase at the Thr68, and the activated CHK2 phosphorylates a number of downstream targets including CDC25, BRCA1, p53, E2F and others that are important in cell cycle checkpoint control, DNA damage repair and DNA-damage-induced apoptosis [1,2,3,4,5]
Summary
CHK2 kinase is an important cell cycle regulator in DNA damage response pathway. In response to exogenous or endogenous DNA damage agents, CHK2 is phosphorylated and activated by ATM kinase at the Thr, and the activated CHK2 phosphorylates a number of downstream targets including CDC25, BRCA1, p53, E2F and others that are important in cell cycle checkpoint control, DNA damage repair and DNA-damage-induced apoptosis [1,2,3,4,5].CHK2 germline mutation was found to associate with a subset of Li-Fraumeni syndrome (LFS), a cancer predisposing familiar syndrome with a majority of patients carrying p53 mutations [6], this notion was challenged by some recent studies [7,8]. CHK2 kinase is an important cell cycle regulator in DNA damage response pathway. Somatic mutations of CHK2 gene have been found in subsets of diverse types of human cancers including breast, lung, vulva, colon, ovary, osteosarcoma, and lymphomas (see review in [9]). The majority of these mutations were missense mutation, base deletion or conversion resulting truncated (page number not for citation purposes). Six homologous sequence fragments at the chromosome 5, 7, 10, 15, 16, 22 and X were found encompassing the exon 10 to 14 of the CHK2 genes and share 95–98% sequence similarity. CHK2-/- cells were remarkably resistant to DNA damage induced apoptosis, mimicking the clinical behavior of non-small cell lung cancer to conventional chemo and radiation therapy
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