Fibroblasts from Li-Fraumeni patients are resistant to low dose-rate irradiation

Sproston, Anthony R; Boyle, John M; Heighway, Jim; Birch, Jillian M; Scott, David

doi:10.1080/095530096145139

Cited by 23 publications

(17 citation statements)

References 17 publications

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“…Fibroblasts from Li-Fraumeni patients show chromosomal sensitivity (measured by an increased frequency of chromosome aberrations) to the effects of ionizing radiation (Parshad et al, 1993), in contrast to the cellular radioresistance (measured by cell survival) observed by Bech-Hansen et al (1981) and our own group (Sproston et al, 1996). Chromosomal radiosensitivity has also been observed in lymphocytes from Li-Fraumeni patients (D Scott, personal communication The above studies were all carried out on relatively earlypassage heterozygous (i.e.…”

Section: Functional Studies Of Li-fraumeni Cellsmentioning

confidence: 98%

Li-Fraumeni syndrome – a molecular and clinical review

Varley

Evans²,

Birch³

1997

Br J Cancer

318

180

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Section: Functional Studies Of Li-fraumeni Cellsmentioning

confidence: 98%

Li-Fraumeni syndrome – a molecular and clinical review

Varley

Evans²,

Birch³

1997

Br J Cancer

318

180

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“…Radiation sensitivity Clonogenic survival after exposure to LDR 6°Co radiation (0.011 Gy min-') was determined as described (Sproston et al, 1996), except that test cells were plated in the absence of feeder cells.…”

Section: Tp53 Statusmentioning

confidence: 99%

“…show patterns of cell survival and permanent G, arrest characteristic of normal cells (Sproston et al, 1996;Williams et al, 1996). To be certain whether or not a mutation is present in 93MA, TP53 should be sequenced, but ethical constraints on sequencing DNA from a normal individual have prevented us from doing this.…”

Section: Genomic Instabilitymentioning

confidence: 99%

“…The most radioresistant strain (2800T) was derived from a blood relative of the affected proband who did not have the codon 245 mutation, but had acquired a mutation in codon 234 during growth in vitro (Mirzayans et al, 1995). Recently, we reported that LFS fibroblasts with TP53 mutations are more resistant than normal fibroblasts to low-dose-rate (LDR) ionizing radiation (Sproston et al, 1996).…”

mentioning

confidence: 99%

“…Cell strains were established and expanded to senescence, during which time changes in chromosome constitution and heterozygosity at TP53 were documented and their radiation sensitivity was determined at early passages. We were particularly interested to know whether increased longevity, chromosome instability and radiation resistance were confined to cells carrying TP53 mutations, and whether Sproston et al (1996). hTwo determinations.…”

mentioning

confidence: 99%

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Chromosome instability is a predominant trait of fibroblasts from Li-Fraumeni families

Boyle

Mitchell²,

Greaves³

et al. 1998

Br J Cancer

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Summary Previous work has indicated a role for p53 in cell cycle control, genomic stability and cellular responses to DNA-damaging agents.However, few data are available for human fibroblasts heterozygous for defined germline mutations in TP53. We report studies on 25 strains derived from 12 families with Li-Fraumeni syndrome (LFS) and 18 strains from normal volunteers. The families include three that are classical LFS families, but in whom no TP53 mutation has been found. In the families with mutations, increased longevity and resistance to low-doserate ionizing radiation showed a statistically significant association with the presence of TP53 mutations. However, not all heterozygotes had increased longevity or were radioresistant, and fibroblasts from cancer-affected members of LFS families without TP53 mutations showed no significant increase in either of these end points. In contrast, all mutation-carrying strains showed evidence of genomic instability, expressed as aneuploidy, and accumulated structural chromosome aberrations in up to 100% of cells, usually accompanied by loss of the wild-type TP53 allele, immediately before senescence. Levels of aneuploidy higher than in normal cells were also observed in fibroblasts from families without TP53 mutations, suggesting that chromosome instability is a major factor in determining the cancer proneness of these families.

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Evaluation of the molecular mechanisms involved in the gain of function of a Li-FraumeniTP53 Mutation

Capponcelli

Pedrini

Cerone³

et al. 2005

Hum. Mutat.

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The TP53 tumor suppressor gene is the most frequent target for genetic alterations in human cancer. TP53 gene alterations may result in the gain of oncogenic functions such as neoangiogenesis and resistance to therapy. The TP53 germ line mutation c.659A>C (p.Y220S) was identified in stored DNA from related patients with Li-Fraumeni syndrome (LFS) who died after developing clinically aggressive tumors. All of the patients were treated with protocols that included doxorubicin hydrochloride (DX) as a pivotal drug. To define the in vitro mutational phenotype of this germ line mutation, we used murine fibroblasts explanted from wild-type (wt) and p53 knockout (KO) mice from the same littermate. p53Y220S and p53R175H fibroblasts, obtained from p53KO fibroblasts transfected with expression vectors encoding the human Y220S and R175H p53 mutants, respectively, exhibited resistance to DX treatment. Moreover, p53Y220S fibroblasts exhibited angiogenetic properties, and after DX treatment, p53Y220S failed to translocate into the nucleus and showed an increase in its cytosolic levels. DX treatment does not influence p53 distribution within the nuclear and cytosolic compartments in p53R175H fibroblasts. Peroxiredoxin II (Prx II), a protein that is involved in eliminating reactive oxygen species (ROS), showed increased expression intensity in p53Y220S fibroblasts after DX treatment, as observed by two-dimensional electrophoresis analysis. Moreover, Thioredoxin (Trx), a protein that cooperates with Prx II, is overexpressed in p53Y220S mutants under basal conditions. These data suggest a relationship between the presence of the p53Y220S mutation and enhanced levels of Prx II and Trx in mutant fibroblasts. Since one of the mechanisms of the DX antitumor effect has been ascribed to production of ROS, future studies will evaluate the involvement of PrxII and Trx in the chemoresistance of p53Y220S fibroblasts to DX.

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Fibroblasts from Li-Fraumeni patients are resistant to low dose-rate irradiation

Cited by 23 publications

References 17 publications

Li-Fraumeni syndrome – a molecular and clinical review

Li-Fraumeni syndrome – a molecular and clinical review

Chromosome instability is a predominant trait of fibroblasts from Li-Fraumeni families

Evaluation of the molecular mechanisms involved in the gain of function of a Li-FraumeniTP53 Mutation

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