Teratogen-induced eye defects mediated by p53-dependent apoptosis

Wubah, Judith A.; Ibrahim, Monier M.; Gao, Xiang; Nguyen, Duy; Pisano, M. Michele; Knudsen, Thomas B.

doi:10.1016/s0960-9822(02)00422-0

Cited by 70 publications

(62 citation statements)

References 35 publications

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“…The ability of the tumor suppressor protein p53 to regulate teratological sensitivity of embryos has been demonstrated in studies with such diverse teratogens as benzo(a)pyrene (Nicol et al 1995), 2-chloro-2 0 -deoxyadenosine (Wubah et al 1996), 4-hydroperoxycyclophosphamide (Moallem & Hales 1998), ionizing radiation (Norimura et al 1996, Wang et al 2000, and diabetes (Pani et al 2002). These studies also provided evidence that both p53-mediated apoptosis and p53-mediated cell arrest may be important steps in the pathogenesis of teratogen-induced anomalies.…”

Section: Introductionmentioning

confidence: 99%

p53 regulates cyclophosphamide teratogenesis by controlling caspases 3, 8, 9 activation and NF-κB DNA binding

Pekar¹,

Molotski²,

Savion³

et al. 2007

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The tumor suppressor protein p53 regulates the sensitivity of embryos to such human teratogens as ionizing radiation, diabetes, and cytostatics. Yet, the molecular mechanisms whereby it fulfills this function remain undefined. We used p53 heterozygous (p53 C/K ) female mice mated with p53 C/K males and then exposed to cyclophosphamide (CP) to test whether caspases 3, 8, and 9 and the transcription factor nuclear factor (NF)-kB may serve as p53 targets. Mice were exposed to CP on day 12 of pregnancy and killed on days 15 and 18 of pregnancy to evaluate CP-induced teratogenic effect. The brain and limbs of embryos harvested 24 h after CP treatment were used to evaluate NF-kB (p65) DNA-binding activity by an ELISA-based method, the activity of the caspases by appropriate colorimetric kits, apoptosis, and cell proliferation by TUNEL, and 5 0 -bromo-2 0 -deoxyuridine incorporation respectively. We observed that the activation of caspases 3, 8, and 9 and the suppression of NF-kB DNA binding following CP-induced teratogenic insult took place only in teratologically sensitive organs of p53 C/C but not p53 K/K embryos. CP-induced apoptosis and suppression of cell proliferation were also more intensive in the former, and they exhibited a higher incidence of structural anomalies, such as open eyes, digit, limb, and tail anomalies. The analysis of the correlations between the p53 embryonic genotype, the activity of the tested molecules, and the CP-induced dysmorphic events at the cellular and organ level suggests caspases 3, 8, and 9 and NF-kB as components of p53-targeting mechanisms in embryos exposed to the teratogen.

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Section: Introductionmentioning

confidence: 99%

p53 regulates cyclophosphamide teratogenesis by controlling caspases 3, 8, 9 activation and NF-κB DNA binding

Pekar¹,

Molotski²,

Savion³

et al. 2007

Reproduction

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“…p53 regulates cell cycle progression and apoptosis in response to cellular stresses such as: DNA damage (Kastan et al, 1991), faulty spindle formation (Minn et al, 1996), depletion of oxygen (Graeber et al, 1996;An et al, 1998), diminution in ribonucleotides (Linke et al, 1996), transcription abnormalities (Andera and and teratogens (Wubah et al, 1996;Nicol et al, 1995). p53 regulates the transcription of downstream eectors, such as the cyclin dependent kinase inhibitor p21 WAF1/CIP1 (p21) and the oncoprotein MDM2 (reviews: Piette et al, 1997;Momand and Zambetti, 1997;Haines, 1997).…”

Section: Introductionmentioning

confidence: 99%

p53 mediated death of cells overexpressing MDM2 by an inhibitor of MDM2 interaction with p53

et al. 1999

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The p53 tumour suppressor is frequently inactivated in human tumours. One form of inactivation results from overexpression of MDM2, that normally forms a negative auto-regulatory loop with p53 and inhibits its activity through complex formation. We have investigated whether disrupting the MDM2-p53 complex in cells that overexpress MDM2 is sucient to trigger p53 mediated cell death. We ®nd that expression of a peptide homologue of p53 that binds to MDM2 leads to increased p53 levels and transcriptional activity. The consequences are increased expression of the downstream eectors MDM2 and p21, inhibition of colony formation, cell cycle arrest and cell death. There is also a decrease in E2F activity, that might have been due to the known physical and functional interactions of MDM2 with E2F1/DP1. However, this decrease is p53 dependent, as are also colony formation, cell cycle arrest and cell death. These results show that a peptide homologue of p53 is sucient to induce p53 dependent cell death in cells overexpressing MDM2, and support the notion that disruption of the p53-MDM2 complex is a target for the development of therapeutic agents.

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“…ADA is expressed in maternal decidual cells, in embryo-derived trophoblast cells, and in giant cells lining the implantation chamber of the embryo (1). Since blocking experiments of ADA resulted in severe growth retardation and death of the embryos by E10.5 (6,38) and ADA has been reported to be regulated by AP-2 transcription factors, we tested whether the level of embryonic ADA is affected by loss of AP-2␥. Because of the close proximity of giant trophoblast cells and the secondary deciduum, it would have been difficult to assess the relative pattern and level of zygotically derived ADA expression in the gestational site.…”

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confidence: 99%

Transcription Factor Gene AP-2γ Essential for Early Murine Development

Werling

Schorle

2002

Molecular and Cellular Biology

168

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Transcription factor gene AP-2␥ belongs to a family of four closely related genes. AP-2␥ had been implicated in multiple functions during proliferation and differentiation based on its expression pattern in trophoblast, neural crest, and ectoderm cells in murine embryos. In order to address the question of the role of AP-2␥ during mammalian development, we generated mice harboring a disrupted AP-2␥ allele. AP-2␥ heterozygous mice are viable and display reduced body sizes at birth but are fertile. Mice deficient for AP-2␥, however, are growth retarded and die at days 7 to 9 of embryonic development. Immunohistochemical analysis revealed that the trophectodermal cells that are found to express AP-2␥ fail to proliferate, leading to failure of labyrinth layer formation. As a consequence, the developing embryo suffers from malnutrition and dies. Analysis of embryo cultures suggests that AP-2␥ is also implicated in the regulation of the adenosine deaminase (ADA) gene, a gene involved in purine metabolism found expressed at the maternal-fetal interface. Therefore, AP-2␥ seems to be required in early embryonic development because it regulates the genetic programs controlling proliferation and differentiation of extraembryonic trophectodermal cells.The AP-2 transcription factor gene family consists of four different genes referred to as AP-2␣, AP-2␤, AP-2␥, and the recently discovered AP-2␦ gene (4,15,17,19,22,37,40). All members of the AP-2 family share a characteristic protein structure containing a unique C-terminal helix-span-helix motif that mediates protein dimerization; together with a basic domain they are involved in DNA binding with varying affinity to GC-rich elements. An N-terminal proline-and glutaminerich region mediates transcriptional activation (33,36).Despite the expression of all AP-2 genes in the extraembryonic trophoblast cells, it remained unclear if there was a redundant function in placental gene regulation. Gene knockout experiments with AP-2␣ and AP-2␤ indicate that the AP-2 proteins carry out individual functions during mouse development. While AP-2␣ is predominantly essential for craniofacial development and ventral body wall closure (29, 39), lack of AP-2␤ leads to polycystic kidney disease (20). Both AP-2␣-and AP-2␤-deficient mice display unaltered implantation and placentation. Is AP-2␥ a key regulator of placental development? Prior to implantation, AP-2␥ is expressed in the trophoblast cells starting at day 3.5 of murine development. After implantation, the expression of AP-2␥ continues in the trophoblast cells and its derivatives, the primary giant cells and the diploid cells of the polar trophectoderm. With ongoing proliferation of the trophoblast cells, AP-2␥ is expressed in the ectoplacental cone and the extraembryonic ectoderm. At the time of chorioallantoic fusion, AP-2␥ expression is increased in all derivatives of the trophoblast lineage (27, 30). Thus, AP-2␥, together with the T-box gene Eomes (26), is the only transcription factor gene found to be expressed in all trophoblast li...

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Teratogen-induced eye defects mediated by p53-dependent apoptosis

Abstract: We conclude that teratogen induction of p53-dependent apoptosis in the developing embryo is positively coupled to the determination of congenital eye defects.

Cited by 70 publications

References 35 publications

p53 regulates cyclophosphamide teratogenesis by controlling caspases 3, 8, 9 activation and NF-κB DNA binding

p53 regulates cyclophosphamide teratogenesis by controlling caspases 3, 8, 9 activation and NF-κB DNA binding

p53 mediated death of cells overexpressing MDM2 by an inhibitor of MDM2 interaction with p53

Transcription Factor Gene AP-2γ Essential for Early Murine Development

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