Epidermal Growth Factor Sensitizes Cells to Ionizing Radiation by Down-regulating Protein Mutated in Ataxia-Telangiectasia

Gueven, Nuri; Keating, Katherine E.; Chen, Phillip; Fukao, Toshiyuki; Khanna, Kum Kum; Watters, Dianne Josephine; Rodemann, P.; Lavin, Martin F.

doi:10.1074/jbc.m006190200

Cited by 51 publications

(46 citation statements)

References 46 publications

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“…These ®ndings are compatible with our results: IGFs are important contributors to the mitogenic e ects of serum (LeRoith et al, 2000), and PHA-stimulation of PBMCs also leads to IGF1R upregulation (Kozak et al, 1987;Hartmann et al, 1992). A more recent report from the same group indicated that EGF can in¯uence ATM expression (Gueven et al, 2001). It was previously known that EGF can enhance or reduce radiosensitivity depending on cell type (Kwok and Sutherland, 1989;Wollman et al, 1994), and antibodymediated blockade of the EGF receptor or HER2 has been shown to increase the radiosensitivity of cancer cells overexpressing these receptors (Huang et al, 1999;Pietras et al, 1999).…”

Section: Discussionsupporting

confidence: 81%

“…It has now been shown that EGF treatment of human ®broblasts and lymphoblasts leads to enhancement of radiosensitivity and downregulation of ATM mRNA and protein expression. This e ect was manifest within hours of EGF treatment (Gueven et al, 2001). We found no evidence that IGF1R downregulation in¯uences B16 melanoma cell expression of Atm at the transcriptional level.…”

Section: Discussionmentioning

confidence: 51%

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Downregulation of the type 1 insulin-like growth factor receptor in mouse melanoma cells is associated with enhanced radiosensitivity and impaired activation of Atm kinase

et al. 2001

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 51%

Downregulation of the type 1 insulin-like growth factor receptor in mouse melanoma cells is associated with enhanced radiosensitivity and impaired activation of Atm kinase

et al. 2001

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“…Soluble factors (eg, granulocyte colony-stimulating factor) restored Atm levels in cells through transcriptional control mechanisms. 31 Injection of cell culture medium did not rescue animals with ALF in our studies. However, this did not exclude the possible role of paracrine factors released by transplanted hepatocytes on other aspects of hepatic recovery.…”

Section: Discussioncontrasting

confidence: 56%

“…27 Also, inhibition of Atm expression by caffeine, a well-characterized ATM kinase inhibitor, 28 significantly increased APAP hepatotoxicity. 29 Because expression of Atm is largely governed by promoter regulation, 30 and is negatively regulated by displacement of positive transcriptional transactivators with soluble factors (eg, epidermal growth factor or hepatocyte growth factor), 31,32 it should be reasonable to consider whether soluble factors will be relevant in DILI and Atm expression and in improvement of Atm expression after cell therapy. For instance, positive regulators of Atm transcription have also been identified (eg, granulocyte colony-stimulating factor), 30 which protects liver from injury by unknown mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Perturbations in Ataxia Telangiectasia Mutant Signaling Pathways After Drug-Induced Acute Liver Failure and Their Reversal During Rescue of Animals by Cell Therapy

Bandi

Joseph

Berishvili

et al. 2011

The American Journal of Pathology

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Superior insights into molecular mechanisms of liver failure, which are not fully understood, will help strategies for inducing liver regeneration. We examined hepatotoxic mechanisms in mice homozygous for the severe combined immune deficiency mutation in the protein kinase, DNA-activated, catalytic polypeptide. Mice were treated with rifampicin, phenytoin, and monocrotaline. The ensuing acute liver failure was characterized by serological, histological, and mRNA studies. Subsequently, we studied whether transplantation of hepatocytes could rescue animals with liver failure. We found extensive liver damage in these animals, with mortality over several days. The expression of multiple hepatic genes was rapidly altered, including those representing pathways in oxidative/metabolic stress, inflammation, DNA damage-repair, and ataxia telangiectasia mutant (Atm) signaling pathways. This led to liver cell growth arrest involving cyclin-dependent kinase inhibitor 1A. Transplantation of hepatocytes with microcarriers in the peritoneal cavity efficiently rescued animals with liver failure. Molecular abnormalities rapidly reversed, including in hepatic Atm and downstream signaling pathways; and residual hepatocytes overcame cyclin-dependent kinase inhibitor 1A-induced cell growth arrest. Reseeding of the liver with transplanted hepatocytes was not required for rescue because native hepatocytes overcame cell growth-arrest to regenerate the liver. This likely resulted from paracrine signaling from hepatocytes in the peritoneal cavity. We concluded that Atm signaling Drug-induced liver injury (DILI) often results in acute liver failure (ALF). 1 Acetaminophen (APAP) is the leading offender in causing ALF; however, despite extensive work, mechanisms of DILI by APAP are incompletely understood. [2][3][4][5] The identification of molecular pathways initiating or amplifying DILI will be highly significant for drug development and for preventing and/or treating ALF. After exposure to hepatotoxic drugs, perturbations in cell stress and toxicity pathways assume prominence. However, more information is required regarding intracellular signaling pathways that impart susceptibility to DILI. Similarly, more information is required regarding failure of liver regeneration in ALF. Nevertheless, establishing these mechanisms has been difficult in the available animal models of ALF. For instance, after exposure to toxic drugs or chemicals, some animals may exhibit rapid and irreversible mortality (eg, within 24 -30 hours after APAP), whereas other animals may recover spontaneously.

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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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Epidermal Growth Factor Sensitizes Cells to Ionizing Radiation by Down-regulating Protein Mutated in Ataxia-Telangiectasia

Cited by 51 publications

References 46 publications

Downregulation of the type 1 insulin-like growth factor receptor in mouse melanoma cells is associated with enhanced radiosensitivity and impaired activation of Atm kinase

Downregulation of the type 1 insulin-like growth factor receptor in mouse melanoma cells is associated with enhanced radiosensitivity and impaired activation of Atm kinase

Perturbations in Ataxia Telangiectasia Mutant Signaling Pathways After Drug-Induced Acute Liver Failure and Their Reversal During Rescue of Animals by Cell Therapy

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

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