p53-dependent apoptosis suppresses radiation–induced teratogenesis

Norimura, Toshiyuki; Nomoto, Satoshi; Katsuki, Motoya; Gondo, Yoichi; Kondo, Sohei

doi:10.1038/nm0596-577

Cited by 234 publications

(124 citation statements)

References 17 publications

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“…We do not assume that a p53 7/7 phenotype would necessarily enhance clonogenic survival thereby promoting propagation of mutants in all cell populations including those that are normally more radiation-resistant. Our ®ndings parallel those reported recently by Norimura et al (1996). These authors report that, following foetal irradiation (at 2 Gy), the total number of abortions and newborn malformations is the same in p53 7/7 versus p53 +/+ mice.…”

Section: Discussionsupporting

confidence: 91%

Absence of p53 permits propagation of mutant cells following genotoxic damage

et al. 1997

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Much evidence has been gathered in support of a critical role for p53 in the cellular response to DNA damage. p53 dysfunction is associated with progression and poor prognosis of many human cancers and with a high incidence of tumours in p53 knockout mice. The absence of a p53-dependent G 1 arrest that facilitates DNA repair or apoptosis might impact critically on clinical cancer in two ways. First, by abrogating the impact on therapy that operates via genotoxic damage and apoptosis; and second, by encouraging progression either by inducing genomic instability and DNA mis-repair or by permitting survival of mutants. However, experiments examining the relationship between p53 de®ciency and mutation frequency have so far failed to con®rm these predictions. The precise role played by p53 is therefore unclear. We now report use of a short term in vitro approach to assess the in¯uence of p53 on radiation-induced mutations at the hprt locus in murine B cell precursors that are normally radiation ultrasensitive. We ®nd a high number of hprt mutants among X-irradiated p53 null cells, which results from preferential survival as clonogenic mutants rather than from a p53-dependent increase in mutation rate. This result has important implications for genotoxic cancer therapy.

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Section: Discussionsupporting

confidence: 91%

Absence of p53 permits propagation of mutant cells following genotoxic damage

et al. 1997

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“…79 This correlation between undifferentiated cell status, high p53 expression and high sensitivity to cell killing was exemplified in a recent study showing that numerous malformed fetuses were generated from p53-null embryos when exposed to X-rays at the blastocyst stage. 80 It is assumed that embryos deficient for p53 are more prone to abnormalities due to their inability to eliminate X-raydamaged cells. Conversely, mouse embryos lacking the mouse-double-minute-2 (MDM2) gene whose protein is a negative regulator of p53 81 were found to die shortly after implantation.…”

Section: Molecular Mechanisms Of Cell Death In the Embryomentioning

confidence: 99%

Apoptosis at the time of embryo implantation in mouse and rat

1999

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The aim of this review is to summarize the information currently available regarding the occurrence of apoptosis in the developing embryo and in the receptive uterus during the peri-implantation period of gestation. Cell death is detected in the inner cell mass of late pre-implantation embryos as the result of an eliminative process that helps trim the embryonic cell lineages of surplus or dysfunctional stem cells. Cell death is also detected in the epiblastic core of early postimplantation embryos, where the process is implicated in the formation of the pro-amniotic cavity. On the maternal side, uterine epithelial cells situated around the attachment site undergo cell death during the initial phase of implantation in order to facilitate embryo anchorage and access to maternal blood supply. Uterine stromal cells closest to the implantation chamber first transform into decidual cells and then commit suicide to make room for the rapidly growing embryo. Although apoptosis is well recognized as a crucial determinant of successful peri-implantation development, our understanding of the cellular and molecular mechanisms regulating this process clearly lags behind the comprehension of cell death control in other systems.

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“…The p53 gene is a tumor suppressor, controlling the cell cycle and apoptosis, 1,2 protecting the irradiated mouse fetus from teratogenesis 3 and regulating mouse reproduction. 4 Mutated p53 is frequently found in human cancers.…”

Section: Introductionmentioning

confidence: 99%

Mutant mouse p53 transgene elevates the chemical induction of tumors that respond to gene silencing with siRNA

Tazaki¹,

Tatsumi²,

Tsuji³

et al. 2009

Cancer Gene Ther

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To study the role of mutant p53 in the induction and cure of tumors, we generated transgenic mice carrying mutant p53 (mp53) containing a 9 bp deletion in exon 6 in addition to wild-type p53, expressing both p53 and mp53. The mp53 cDNA was cloned from a radiation-induced mouse tumor and ligated to the chicken b-actin promoter/CMV-IE enhancer in the expression vector. The presence of mp53 suppressed p21 expression in primary fibroblasts after ionizing irradiation, indicating the dominant-negative activity of mp53 in the mice. These mice developed fibrosarcomas after the subcutaneous injection of 3-methylcholanthrene with an incidence 1.7-fold higher than that of wild-type mice (42% excess). The tumors were then treated via a potent atelocollagen delivery system with small interfering RNA (siRNA), that targeted the promoter/enhancer of the expression vector, resulting in the suppression of tumor growth in 30% of 44 autochthonous tumors, including four cures, and their transplants, the total fraction corresponding to the tumor excess. This suppressive effect involved the induction of apoptosis. These results indicate that mp53 activity causes tumors that can be suppressed by subsequent silencing of mp53 in the presence of wild-type p53 alleles.

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p53-dependent apoptosis suppresses radiation–induced teratogenesis

Cited by 234 publications

References 17 publications

Absence of p53 permits propagation of mutant cells following genotoxic damage

Absence of p53 permits propagation of mutant cells following genotoxic damage

Apoptosis at the time of embryo implantation in mouse and rat

Mutant mouse p53 transgene elevates the chemical induction of tumors that respond to gene silencing with siRNA

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