Epidermal Growth Factor Abrogates Hypoxia-Induced Apoptosis in Cultured Human Trophoblasts through Phosphorylation of BAD Serine 112

Humphrey, Rachel; Sonnenberg-Hirche, Christina; Smith, Steven D.; Hu, Chaobin; Barton, Aaron; Sadovsky, Yoel; Nelson, D. Michael

doi:10.1210/en.2007-1253

Cited by 28 publications

(20 citation statements)

References 44 publications

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“…BID and BAD have been described to be upregulated or downregulated by hypoxia depending on the study [39], [40], [44]. Finally, hypoxia reduces BAD phosphorylation on Ser112 but increases its phosphorylation on Ser136 and Ser155 [45], [46]. Since hypoxia has frequently been described to affect BCL-2 family protein abundance, their protein expression level was assessed by western blot.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Induced Modulation of Apoptosis and BCL-2 Family Proteins in Different Cancer Cell Types

et al. 2012

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Hypoxia plays an important role in the resistance of tumour cells to chemotherapy. However, the exact mechanisms underlying this process are not well understood. Moreover, according to the cell lines, hypoxia differently influences cell death. The study of the effects of hypoxia on the apoptosis induced by 5 chemotherapeutic drugs in 7 cancer cell types showed that hypoxia generally inhibited the drug-induced apoptosis. In most cases, the effect of hypoxia was the same for all the drugs in one cell type. The expression profile of 93 genes involved in apoptosis as well as the protein level of BCL-2 family proteins were then investigated. In HepG2 cells that are strongly protected against cell death by hypoxia, hypoxia decreased the abundance of nearly all the pro-apoptotic BCL-2 family proteins while none of them are decreased in A549 cells that are not protected against cell death by hypoxia. In HepG2 cells, hypoxia decreased NOXA and BAD abundance and modified the electrophoretic mobility of BIMEL. BIM and NOXA are important mediators of etoposide-induced cell death in HepG2 cells and the hypoxia-induced modification of these proteins abundance or post-translational modifications partly account for chemoresistance. Finally, the modulation of the abundance and/or of the post-translational modifications of most proteins of the BCL-2 family by hypoxia involves p53-dependent and –independent pathways and is cell type-dependent. A better understanding of these cell-to-cell variations is crucial in order to overcome hypoxia-induced resistance and to ameliorate cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Hypoxia-Induced Modulation of Apoptosis and BCL-2 Family Proteins in Different Cancer Cell Types

et al. 2012

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“…BAD is a proapoptotic member of the Bcl-2 family that is sequestered in the cytoplasm of cytotrophoblasts by 14-3-3 proteins when phosphorylated at Ser 112 (15). As hypoxia reduced levels of p53 in syncytiotrophoblasts yet increased apoptosis, we surmised that the apoptosis involved a non-p53-dependent mechanism.…”

Section: Confirmation Of the Syncytiotrophoblast Paradigmmentioning

confidence: 91%

Hypoxia downregulates p53 but induces apoptosis and enhances expression of BAD in cultures of human syncytiotrophoblasts

Chen

Longtine

Sadovsky

et al. 2010

American Journal of Physiology-Cell Physiology

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Hypoxia is commonly assigned a role in the placental dysfunction characteristic of preeclampsia and intrauterine growth restriction. We previously showed that hypoxia upregulates p53 and enhances apoptosis in primary cultures of human cytotrophoblasts. Here we tested the hypothesis that hypoxia also induces apoptosis in syncytiotrophoblasts by upregulation of p53. Primary cultures of human cytotrophoblasts that had differentiated into syncytiotrophoblasts by 52 h were exposed for ≤24 h to 20% or <1% oxygen in the presence or absence of staurosporine or the p53 modulators nutlin-3, pifithrin-α, and pifithrin-μ. Proteins were detected by Western blot analysis or immunofluorescence. Compared with 20% oxygen, exposure of syncytiotrophoblasts to <1% oxygen upregulated hypoxia-inducible factor (HIF)-1α and rapidly downregulated p53. Activity of p53 in hypoxic syncytiotrophoblasts was reduced by the higher expression of the negative p53 regulator MDMX and by the reduction of phosphorylation of p53 at Ser(392), which reduces p53 activity. Conversely, staurosporine, a kinase inhibitor, and nutlin-3, a drug that enhances p53 expression, both raised p53 levels and increased the rate of apoptosis in syncytiotrophoblasts compared with vehicle controls. Immunofluorescence staining showed p53 immunolocalized to both cytoplasm and nuclei of nutlin-3-exposed syncytiotrophoblasts. The hypoxia-induced apoptosis in syncytiotrophoblasts correlated with enhanced expression of the proapoptotic BAD and a reduced level of antiapoptotic BAD phosphorylated on Ser(112). We surmise that cell death induced by extreme hypoxia in syncytiotrophoblasts follows a non-p53-dependent pathway, unlike that of a nonhypoxic stimulus and unlike hypoxic cytotrophoblasts. We speculate that downregulation of p53 activity in response to hypoxia reduces or eliminates the apoptosis transduced by the p53 pathway in syncytiotrophoblasts, thereby limiting cell death and maintaining the integrity of this critical villous component.

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“…Importantly, in cytotrophoblasts, epidermal growth factor reverses the hypoxia-induced decrease in phosphorylation of Bad at serine 112. Bad phosphorylated at this residue is sequestered by cytoplasmic 14-3-3 proteins so that translocation of Bad to mitochondria does not occur and apoptosis is not induced [67]. Collectively, these results show that the response of term trophoblasts to hypoxia is phenotype dependent and in cytotrophoblasts involves elevated p53 activity, increases in pro-apoptotic Bcl-2 proteins, and decreases in anti-apoptotic Bcl-2 proteins.…”

Section: Trophoblast Responses To Hypoxia Include Apoptosis and Aumentioning

confidence: 98%

Review: Oxygen and trophoblast biology – A source of controversy

2011

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Oxygen is necessary for life yet too much or too little oxygen is toxic to cells. The oxygen tension in the maternal plasma bathing placental villi is <20 mm Hg until 10–12 weeks’ gestation, rising to 40–80 mmHg and remaining in this range throughout the second and third trimesters. Maldevelopment of the maternal spiral arteries in the first trimester predisposes to placental dysfunction and sub-optimal pregnancy outcomes in the second half of pregnancy. Although low oxygen at the site of early placental development is the norm, controversy is intense when investigators interpret how defective transformation of spiral arteries leads to placental dysfunction during the second and third trimesters. Moreover, debate rages as to what oxygen concentrations should be considered normal and abnormal for use in vitro to model villous responses in vivo. The placenta may be injured in the second half of pregnancy by hypoxia, but recent evidence shows that ischemia with reoxygenation and mechanical damage due to high flow contributes to the placental dysfunction of diverse pregnancy disorders. We overview normal and pathologic development of the placenta, consider variables that influence experiments in vitro, and discuss the hotly debated question of what in vitro oxygen percentage reflects the normal and abnormal oxygen concentrations that occur in vivo. We then describe our studies that show cultured villous trophoblasts undergo apoptosis and autophagy with phenotype-related differences in response to hypoxia.

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Epidermal Growth Factor Abrogates Hypoxia-Induced Apoptosis in Cultured Human Trophoblasts through Phosphorylation of BAD Serine 112

Cited by 28 publications

References 44 publications

Hypoxia-Induced Modulation of Apoptosis and BCL-2 Family Proteins in Different Cancer Cell Types

Hypoxia-Induced Modulation of Apoptosis and BCL-2 Family Proteins in Different Cancer Cell Types

Hypoxia downregulates p53 but induces apoptosis and enhances expression of BAD in cultures of human syncytiotrophoblasts

Review: Oxygen and trophoblast biology – A source of controversy

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