ATM (ataxia-telangiectasia mutated) gene plays a central role in the DNA-damage response pathway. We characterized the ATM protein expression in immortalized cells from AT and AT-variant patients, and heterozygotes and correlated it with two ATM-dependent radiation responses, Gf checkpoint arrest and p53-Ser 15 phosphorylation. On Western blots, the full-length ATM protein was detected in eight of 18 AT cases, albeit at 1-32% of the normal levels, whereas a truncated ATM protein was detected in a single case, despite the prevalence among cases of truncation mutations. Of two ataxia without telangiectasia [A-(T)] cases, one expressed 20% and the other similar to 70% or the normal ATM levers. Noteworthy, among ten asymptomatic heterozygous carriers for AT, normal amounts of ATM protein were found in one and reduced by 40-50% in the remaining cases. The radiation-induced phosphorylation of p53 protein at serine 15, largely mediated by ATM kinase, was defective in AT, A(-T) and in 2/4 heterozygous carriers, while the G1 cell cycle checkpoint was disrupted in all AT and A(-T) cases, and in 3/10 AT heterozygotes. Altogether, our study shows that AT and A(-T) cases bearing truncation mutations of the ATM gene can produce modest amounts of full-length (and only rarely truncated) ATM protein. However, this limited expression of ATM protein provides no benefit regarding the ATM-dependent responses related to G1 arrest and p53-ser15 phosphorylation. Our study additionally shows that the majority of AT heterozygotes express almost halved revels of ATM protein, sufficient in most cases to normally regulate the ATM-dependent DNA damage-response pathway. (C) 2000 Cancer Research Campaign.

ATM protein and p53-serine 15 phosphorylation in ataxia-telangiectasia (AT) patients and at heterozygotes / D., Delia; S., Mizutani; S., Panigone; E., Tagliabue; E., Fontanella; M., Asada; T., Yamada; Y., Taya; Sabrina, Prudente; S., Saviozzi; Frati, Luigi; M. A., Pierotti; Chessa, Luciana. - In: BRITISH JOURNAL OF CANCER. - ISSN 0007-0920. - STAMPA. - 82:12(2000), pp. 1938-1945. [10.1054/bjoc.2000.1168]

ATM protein and p53-serine 15 phosphorylation in ataxia-telangiectasia (AT) patients and at heterozygotes

Sabrina Prudente;FRATI, Luigi;CHESSA, Luciana
2000

Abstract

ATM (ataxia-telangiectasia mutated) gene plays a central role in the DNA-damage response pathway. We characterized the ATM protein expression in immortalized cells from AT and AT-variant patients, and heterozygotes and correlated it with two ATM-dependent radiation responses, Gf checkpoint arrest and p53-Ser 15 phosphorylation. On Western blots, the full-length ATM protein was detected in eight of 18 AT cases, albeit at 1-32% of the normal levels, whereas a truncated ATM protein was detected in a single case, despite the prevalence among cases of truncation mutations. Of two ataxia without telangiectasia [A-(T)] cases, one expressed 20% and the other similar to 70% or the normal ATM levers. Noteworthy, among ten asymptomatic heterozygous carriers for AT, normal amounts of ATM protein were found in one and reduced by 40-50% in the remaining cases. The radiation-induced phosphorylation of p53 protein at serine 15, largely mediated by ATM kinase, was defective in AT, A(-T) and in 2/4 heterozygous carriers, while the G1 cell cycle checkpoint was disrupted in all AT and A(-T) cases, and in 3/10 AT heterozygotes. Altogether, our study shows that AT and A(-T) cases bearing truncation mutations of the ATM gene can produce modest amounts of full-length (and only rarely truncated) ATM protein. However, this limited expression of ATM protein provides no benefit regarding the ATM-dependent responses related to G1 arrest and p53-ser15 phosphorylation. Our study additionally shows that the majority of AT heterozygotes express almost halved revels of ATM protein, sufficient in most cases to normally regulate the ATM-dependent DNA damage-response pathway. (C) 2000 Cancer Research Campaign.
2000
ataxia-telangiectasia; atm; cell cycle
01 Pubblicazione su rivista::01a Articolo in rivista
ATM protein and p53-serine 15 phosphorylation in ataxia-telangiectasia (AT) patients and at heterozygotes / D., Delia; S., Mizutani; S., Panigone; E., Tagliabue; E., Fontanella; M., Asada; T., Yamada; Y., Taya; Sabrina, Prudente; S., Saviozzi; Frati, Luigi; M. A., Pierotti; Chessa, Luciana. - In: BRITISH JOURNAL OF CANCER. - ISSN 0007-0920. - STAMPA. - 82:12(2000), pp. 1938-1945. [10.1054/bjoc.2000.1168]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/383573
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