Rapid radiation-induction of ATM protein levels in situ

Fang, ZM; Cs, Lee; Sarris, Maria; Jh, Kearsley; Murrell, Dédée F.; Lavin, Martin F.; Keating, Katherine E.; Clarke, Raymond A.

doi:10.1080/00313020125667

Cited by 15 publications

(13 citation statements)

References 29 publications

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“…Conversely, one tumor (BrCaT15) that was found to harbor methylated ATM promoter as judged by MSP exhibits only a modest reduction in ATM mRNA abundance. Others have observed that, in some cell types, ionizing radiation or growth factors can exert effects on ATM gene expression through alterations in rates of gene transcription (Fang et al, 2001;Gueven et al, 2001). Although the ATM promoter contains several canonical …”

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confidence: 99%

The ATM gene is a target for epigenetic silencing in locally advanced breast cancer

Kim

Cvitanovic

et al. 2004

Oncogene

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Several epidemiological studies on ataxia-telangiectasia families indicate that obligate ATM heterozygotes display an elevated risk for developing breast cancer. However, a molecular basis for a potential link between diminished ATM function and sporadic breast malignancy remains elusive. Here, we show that 78% (18 out of a panel of 23) of surgically removed breast tumors (stage II or greater) displayed aberrant methylation of the ATM proximal promoter region as judged by methylation-specific PCR. Aberrant methylation of the ATM promoter was independently confirmed in several tumors by bisulfite sequencing. Moreover, bisulfite sequencing indicated that this region of the genome is subject to dense methylation. Further, we found a highly significant correlation (P ¼ 0.0006) between reduced ATM mRNA abundance, as measured by realtime RT-PCR, and aberrant methylation of the ATM gene promoter. These findings indicate that epigenetic silencing of ATM expression occurs in locally advanced breast tumors, and establish a link at the molecular level between reduced ATM function and sporadic breast malignancy. Oncogene (2004Oncogene ( ) 23, 9432-9437. doi:10.1038 Published online 1 November 2004Keywords: ATM; epigenetics; promoter hypermethylation; breast cancer Germline mutation of the ATM gene is the underlying cause of the cancer-prone disorder ataxia-telangiectasia (A-T) (Rotman and Shiloh, 1998). As outlined in the seminal work of Swift et al. (1987), and validated in subsequent studies (Easton, 1994;Athma et al., 1996), obligate ATM heterozygotes display an approximate fourfold elevated risk for developing breast cancer. Following the cloning of the ATM gene, several groups (FitzGerald et al., 1997;Bebb et al., 1999;Shafman et al., 2000) studied large cohorts of sporadic breast cancer patients and age-matched controls for nonsense or frame-shift mutations within the ATM gene. Neither group found evidence for a higher incidence of defective ATM alleles in the cancer patient cohort. Furthermore, the correlation between breast cancer and dominantnegative forms of ATM arising from defined missense or intronic mutations within the ATM gene remains controversial (Chenevix-Trench et al., 2002;Bernstein et al., 2003). Thus, a potential role for diminished ATM function in sporadic breast cancer remains unresolved.We have reported that, in cultured tumor cells, the ATM gene is subject to epigenetic silencing attributable to aberrant methylation of its proximal promoter region (Kim et al., 2002). More recently, we determined that aberrant methylation of the ATM promoter occurs in a subset of head and neck tumors (Ai et al., 2004). Further, several reports showed that reduced ATM expression, as judged by immunohistochemical staining, occurs in a significant portion of breast tumors (Kairouz et al., 1999;Angele et al., 2000). Collectively, these findings led us to hypothesize that epigenetic events, rather than somatic mutation of the ATM gene itself, link reduced ATM function to sporadic breast cancer.The putative proximal pro...

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confidence: 99%

The ATM gene is a target for epigenetic silencing in locally advanced breast cancer

Kim

Cvitanovic

et al. 2004

Oncogene

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“…Therefore, it is expected that differences in the reliance of cells on these two distinct forms of DSB repair in different cell types would significantly affect tumour susceptibility. Although there is currently no direct evidence for this hypothesis, levels of DNA-PKcs and Ku80 show a high degree of cell-type-specific expression and posttranslational regulation of activity in human tissues [38][39][40]. Furthermore, analysis of damage sensitivity in transgenic mice suggests specialized roles for HR and NHEJ following exposure to different genotoxic agents and changes in the relative contributions of these repair mechanisms during development [41].…”

Section: Repair Mechanismsmentioning

confidence: 99%

Cell and tissue responses to genotoxic stress

Coates

Lorimore

Wright

2005

The Journal of Pathology

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Cancers arise as a consequence of the accumulation of multiple genetic mutations in a susceptible cell, resulting in perturbation of regulatory networks that control proliferation, survival, and cellular function. Here, the sources of cellular stress that can cause oncogenic mutations and the responses of cells to DNA damage are reviewed. The role of different repair pathways and the potential for cell-and tissue-specific reliance on individual repair mechanisms are discussed. Evidence for cell-and tissue-specific activation of p53-mediated growth arrest and apoptosis after exposure to an individual genotoxin is assessed and some of the potential mediators of these different responses are provided. These cell-and tissuespecific responses to particular forms of DNA damage are likely to be key determinants of tissue-specific tumour susceptibility, and there is good evidence for genetic variations in these responses. The role that genotoxic agents play in altering the microenvironment to produce indirect effects on tumourigenesis through altered production of free radicals and cytokines that are characteristic of inflammatory-type processes is also evaluated. Changes to the microenvironment as direct or indirect effects of genotoxic stress can be involved in both tumour initiation and progression and may even be a prerequisite for tumourigenesis. Therefore, tumour susceptibility after endogenous or exogenous genotoxic stress represents a balance between cell-intrinsic responses of target cells and changes to the microenvironment. A fuller understanding of cell-and tissue-specific responses, alterations to the microenvironment, and genetic modifiers of these responses could lead to novel prevention and therapeutic strategies for common forms of human malignancy.

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“…In the presence of DNA DSB damage, ATM phosphorylates a variety of protein targets and activates several different signaling cascades (Figure 2). In contrast to the mRNA, ATM protein does become more abundant in response to IR, although only in cells such as lymphocytes that express low basal levels: no change is seen in cells expressing high levels of ATM (Fang et al, 2001). In addition, ATM becomes more tightly attached to the nuclear matrix and/or chromatin in the presence of DNA damage (Andegeko et al, 2001).…”

Section: The Proteinmentioning

confidence: 99%