Regulation of Chk2 gene expression in lymphoid malignancies: involvement of epigenetic mechanisms in Hodgkin's lymphoma cell lines

Kato, Naoko; Fujimoto, Hiroko; Yoda, Akinori; Oishi, Isao; Matsumura, Nobutoshi; Kondo, Takeshi; Tsukada, Junichi; Tanaka, Yoshiya; Imamura, Masahiro; Minami, Yasuhiro

doi:10.1038/sj.cdd.4401461

Cited by 24 publications

(14 citation statements)

References 58 publications

(66 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, while CHEK2 LOH was associated with loss or reduction of protein expression in all the tumors studied, 1100delC was not significantly more frequent in tumors showing LOH at the CHEK2 locus, which suggests that there may be also other mechanisms of inactivation. Methylation of CHEK2 has CHEK2 in familial breast cancer H Nevanlinna and J Bartek not been observed in breast carcinomas with downregulation of CHEK2 mRNA expression , however, epigenetic silencing of CHEK2 gene has been observed in Non-Hodgkin's lymphoma cell lines with drastic reduction of CHEK2 expression but no identified mutations (Kato et al, 2004). In breast cancer, Staalesen et al (2004) has detected a very large number of tumor-specific splice variants, in addition to normal length mRNA, in all stage III breast tumors studied.…”

Section: Tumors From Chek2 Mutation Carriers -Chek2 In Tumorsmentioning

confidence: 99%

The CHEK2 gene and inherited breast cancer susceptibility

2006

View full text Add to dashboard Cite

Checkpoint kinase 2 (CHEK2, Chk2) emerges as an important signal transducer of cellular responses to DNA damage and a candidate tumor suppressor whose defects contribute to molecular pathogenesis of diverse types of human malignancies, both sporadic and hereditary. Here, we briefly outline the molecular properties, regulation and physiological role of CHEK2, and review in more detail its defects that predispose to tumors, with particular emphasis on familial breast cancer. The frequency, penetrance and epidemiological as well as clinical significance of the two most studied breast cancerpredisposing variants of the CHEK2 gene, 1100delC and I157T, are highlighted in more depth, and additional CHEK2 mutations and their cancer relevance are discussed as well. These recent findings are considered also from a broader perspective of CHEK2 as the integral component of the ataxia telangiectasia-mutated-CHEK2-p53 pathway within the genome integrity maintenance system and a barrier against tumor progression. Finally, the potential value of information about the CHEK2 status in family counseling and optimizition of individualized cancer treatment is discussed.

show abstract

Section: Tumors From Chek2 Mutation Carriers -Chek2 In Tumorsmentioning

confidence: 99%

The CHEK2 gene and inherited breast cancer susceptibility

2006

View full text Add to dashboard Cite

show abstract

“…Mutations within the Chk2 gene have been identified in a variant form of Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype normally associated with p53 mutations, and in sporadic human cancers (3,29). Aberrant epigenetic regulation of Chk2 gene expression was also found in several cell lines from lymphoid malignancies (30). Recently, it has been shown that accumulation of phosphorylated Chk2 and enhanced apoptosis are found in early precursor lesions of tumors, indicating that Chk2 functions as an anti-cancer barrier at early stages of tumorigenesis (31,32).…”

mentioning

confidence: 98%

Intrinsic Kinase Activity and SQ/TQ Domain of Chk2 Kinase as Well as N-terminal Domain of Wip1 Phosphatase Are Required for Regulation of Chk2 by Wip1

Yoda

Onishi

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

). Here, we performed structure-function analyses of Chk2 and Wip1 by using a series of deletion or amino acid-substituted mutant proteins of Chk2 and Wip1. We show that nuclear localization of both Chk2 and Wip1 is required for their association in cultured cells and that the serine-glutamine (SQ)/threonine-glutamine (TQ) domain of Chk2, containing Thr-68, and the N-terminal domain of Wip1, comprising about 100 amino acids, are necessary and sufficient for the association of both molecules. However, it was found that an intrinsic kinase activity of Chk2, but not phosphatase activity of Wip1, is required for the association of fulllength Chk2 and Wip1. Interestingly, we also show that the mutant Wip1 proteins, bearing the N-terminal domain of Wip1 alone or lacking an intrinsic phosphatase activity, exhibit dominant negative effects on the functions of the wild-type Wip1, i.e. ectopic expression of either of these Wip1 mutants inhibits dephosphorylation of Thr-68 in Chk2 by Wip1 and anti-apoptotic function of Wip1. These results provide a molecular basis for developing novel anti-cancer drugs, targeting oncogenic Wip1 phosphatase.

show abstract

“…Furthermore, the possibility that CHEK2 might be silenced through promoter methylation has only been investigated in lung (7), lymphoid (8,9), vulval (10), and breast cancers (11), with only two of these studies (8,11) doing combined genetic and epigenetic analyses. Consequently, the aim of this study was to determine the frequency of genetic or epigenetic alterations of CHEK2 in sporadic breast, ovarian, and colon cancers.…”

mentioning

confidence: 99%

Genetic and Epigenetic Analysis of CHEK2 in Sporadic Breast, Colon, and Ovarian Cancers

Williams

Choong

Johnson

et al. 2006

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Germ-line variants in CHEK2 have been associated with increased breast, thyroid, prostate, kidney, and colorectal cancer risk; however, the prevalence of somatic inactivation of CHEK2 in common cancer types is less clear. The aim of this study was to determine if somatic mutation and/or epigenetic modification play a role in development of sporadic breast, colon, or ovarian cancers. Experimental Design: We undertook combined genetic and epigenetic analysis of CHEK2 in sporadic primary breast, ovarian, and colon tumors [all exhibiting chromosome 22q loss of heterozygosity (LOH)] and cancer cell lines. Expression of Chk2 was assessed by immunohistochemistry in 119 ovarian tumors. Results: Two novel germ-line variants were identified; however, none of the primary tumors harbored somatic mutations.Two CpG clusters previously implicated in CHEK2 silencing were investigated for evidence of hypermethylation. No methylation was detected at the distal CpG island. The proximal CpG cluster was methylated in all tumor and normal DNA, suggesting that this might not represent a true CpG island and is not relevant in the control of CHEK2 expression. Twenty-three percent of ovarian tumors were negative for Chk2 protein by immunohistochemistry, but there was no significant correlation between LOH across the CHEK2 locus and intensity of Chk2 staining (P = 0.12). Conclusions: LOH across the CHEK2 locus is common in sporadic breast, ovarian, and colorectal cancers, but point mutation or epigenetic inactivation of the retained allele is uncommon. Loss of Chk2 protein in ovarian cancer was not associated with allelic status, suggesting that inactivation does not occur as a consequence of haploinsufficiency.The CHEK2 gene has recently been identified as a breast cancer susceptibility gene (1 -3), and some germ-line variants may increase the risk of colorectal, thyroid, prostate, and kidney cancer in specific populations (4, 5). CHEK2 encodes the human homologue of the Cds1 and RAD53 checkpoint kinases and plays a central role in the DNA damage checkpoint pathway. In response to ionizing radiation-induced DNA damage, Chk2 is activated by the ataxia-telangiectasia mutated (ATM) protein and subsequently phosphorylates several substrates, including p53, BRCA1, Mdm2, Cdc25A, and Cdc25C, leading to cell cycle arrest, activation of DNA repair mechanisms, or apoptosis. Activated Chk2 has been identified in early precursor lesions of urinary bladder, breast, lung, and colon carcinomas (but not in normal tissues) before the occurrence of genomic instability and malignant conversion (6), suggesting that DNA damage checkpoints are activated in the early stages of tumorigenesis. Therefore, mutations in CHEK2, or other genes involved in the ATM-Chk2-p53 pathway, may allow tumorigenic cells to evade normal cell cycle checkpoints, leading to aberrant cell proliferation and survival, increased genomic instability, and ultimately tumor progression.Although numerous studies have investigated for CHEK2 germ-line mutations in high-risk c...

show abstract

Regulation of Chk2 gene expression in lymphoid malignancies: involvement of epigenetic mechanisms in Hodgkin's lymphoma cell lines

Cited by 24 publications

References 58 publications

The CHEK2 gene and inherited breast cancer susceptibility

The CHEK2 gene and inherited breast cancer susceptibility

Intrinsic Kinase Activity and SQ/TQ Domain of Chk2 Kinase as Well as N-terminal Domain of Wip1 Phosphatase Are Required for Regulation of Chk2 by Wip1

Genetic and Epigenetic Analysis of CHEK2 in Sporadic Breast, Colon, and Ovarian Cancers

Contact Info

Product

Resources

About