Enhanced Basal Apoptosis in Cultured Term Human Cytotrophoblasts is Associated with a Higher Expression and Physical Interaction of p53 and Bak

Hu, Chaobin; Smith, Steven D.; Pang, Liyi; Sadovsky, Yoel; Nelson, D. Michael

doi:10.1016/j.placenta.2005.11.004

Cited by 26 publications

(20 citation statements)

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“…Altogether, our findings demonstrate that p53 is essential for Ara-C-induced trophoblastic apoptosis, and they suggest that p53 triggers apoptosis by upregulating transcription of its target genes, some of which have pro-apoptotic functions. In addition, because increased production of p53 protein is observed in human placentas in abnormal pregnancies [30][31][32][33], our results raise the possibility that p53 is involved in the pathogenesis of placental disorders through the induction of trophoblastic apoptosis.…”

Section: Discussionmentioning

confidence: 88%

“…Recent investigations have shown that more p53 protein is produced by the human placentas in abnormal pregnancies; thus, p53 is suspected of contributing to the pathogenesis of placental disorders through the induction of trophoblastic apoptosis [30][31][32][33]. We previously demonstrated that administration of the DNA-damaging agents ethylnitrosourea and cytosine arabinoside (Ara-C) to pregnant rats induced apoptosis of trophoblasts in the placental labyrinth zone, with upregulation of p53 protein production [15,16].…”

Section: Introductionmentioning

confidence: 99%

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Essential role of p53 in trophoblastic apoptosis induced in the developing rodent placenta by treatment with a DNA-damaging agent

et al. 2007

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Placental apoptosis plays important roles in both normal morphogenesis and pathogenesis. We previously reported that administration of cytosine arabinoside (Ara-C), a DNA-damaging agent, to pregnant rats induced apoptosis of trophoblasts in the placental labyrinth zone. Our aim here was to clarify the molecular pathway of DNA damage induced-trophoblastic apoptosis. We found the accumulation and phosphorylation of p53 protein, a tumor suppressor that mediates apoptosis under various cellular stresses, in Ara-C-treated rat placentas. Expression of the mRNAs of downstream targets of p53 was upregulated, suggesting that p53 exerts its function as a transcription factor. We also observed release of mitochondrial cytochrome c and activation of caspase-9, hallmarks of the intrinsic apoptotic pathway. Phosphorylation of Chk1 and H2A.X, target substrates of DNA damage transducers, was detected immediately after Ara-C treatment, suggesting activation of DNA damage cascades to phosphorylate p53. Ara-C-induced trophoblastic apoptosis was almost completely abrogated in placentas of Trp53 (coding p53)-deficient mice, whereas the levels of physiological apoptosis in trophoblasts were similar among wild-type and Trp53-deficient mice. These results indicate that p53 is essential for DNA damage-induced trophoblastic apoptosis and suggest that the mechanisms that regulate the damage-induced apoptosis differ from those that regulate physiological apoptosis.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Essential role of p53 in trophoblastic apoptosis induced in the developing rodent placenta by treatment with a DNA-damaging agent

et al. 2007

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“…30,31 This was also agreed with the protein-protein interaction between p53 and Bak, were likely to contribute to a higher level of apoptosis. 32 We next observed the expression level of p53 in HPV-11E6 expressing cells by Western blot analysis. The results showed that p53 was increased in HPV-11E6 expressing cells compared with control (Fig.…”

Section: Subcellular Location Of Hpv-11e6 Proteinmentioning

confidence: 99%

Two different HPV-11E6 fusion proteins trap p53 in the cytoplasm and induce apoptosis

Sun

Zhang²,

Lei³

et al. 2008

Cancer Biology & Therapy

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Mucosal high risk human papillomaviruses (HPVs) have been shown to be the major cause of cervical cancer. However, the reason why the low risk HPVs only cause proliferative but non-invasive lesions of infected epithelia remains elusive. Because p53 interacts with high risk HPVs E6 and plays a very important role in carcinogenesis, it is assumed that low risk HPVs E6 might interact with p53 in a different pattern. We used mammalian green fluorescent protein (GFP) tagged and polyhistidine (His) tagged proteins expression systems to express HPV-11E6 fusion proteins in wild-type (wt) p53 cell lines, such as 293T and MCF-7 cells to trace the traffic and location of E6s and p53. We showed that: (1) Following transfection, HPV-11E6 was predominantly expressed in the cytoplasm; (2) Using immunocytochemistry and Western blotting, endogenous wt p53 was shown to be trapped in cytoplasm by HPV-11E6 expression. (3) Apoptosis was increased in HPV-11E6 expressed cells. In conclusion, the entrapment of endogenous wt p53 in cytoplasm by the low risk HPV-11E6 may be one of the reasons why low risk HPV is not able to induce malignant transformation.

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“…Another key set of proteins regulating apoptosis in human trophoblasts is the members of the BCL2 family (10,17,18). To determine if multiple apoptotic pathways are affected by punicalagin, we examined its effect on BCL2 family members.…”

Section: Resultsmentioning

confidence: 99%

Punicalagin, a polyphenol in pomegranate juice, downregulates p53 and attenuates hypoxia-induced apoptosis in cultured human placental syncytiotrophoblasts

Chen

Longtine

Nelson

2013

American Journal of Physiology-Endocrinology and Metabolism

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Chen B, Longtine MS, Nelson DM. Punicalagin, a polyphenol in pomegranate juice, downregulates p53 and attenuates hypoxia-induced apoptosis in cultured human placental syncytiotrophoblasts. Am J Physiol Endocrinol Metab 305: E1274 -E1280, 2013. First published October 1, 2013; doi:10.1152/ajpendo.00218.2013.-Oxidative stress is associated with placental dysfunction and suboptimal pregnancy outcomes. Therapeutic interventions to limit placental injury from oxidative stress are lacking. Punicalagin is an ellagitannin and a potent antioxidant in pomegranate juice. We showed that both pomegranate juice and punicalagin decrease oxidative stress and apoptosis in cultured syncytiotrophoblasts. p53 is involved in the oxidative stress-induced apoptosis in trophoblasts. We now test the hypothesis that punicalagin limits trophoblast injury in vitro by regulating the levels of p53. We examined the expression of p53, mouse double minute 2 homolog, p21, hypoxia-inducible factor (HIF) ␣, and selected members of the B cell lymphoma 2 (BCL2) family of proteins in cultured syncytiotrophoblasts exposed to Յ1% oxygen in the absence or presence of punicalagin. We found that punicalagin attenuated hypoxia-induced apoptosis in syncytiotrophoblasts, as quantified by levels of cleaved poly-ADP ribose polymerase. This protective effect was in part mediated by reduced p53 activity shown by decreased expression of p21, lower HIF1␣ expression, and limited activity of caspases 9 and 3. There was no change in expression of proteins in the BCL2 family, which are also important in apoptosis. The data support a role for downregulation of p53 in the protection of human trophoblasts by punicalagin. placenta; hypoxia-inducible factor ␣; mouse double minute 2 homolog UP TO 600,000 PREGNANCIES annually in the United States are at risk for preeclampsia, intrauterine growth restriction (IUGR), or both maladies. Preeclampsia and IUGR often share a placental histopathology that includes improper remodeling of the maternal spiral arteries (7,8). The inferred physiological effect of this maladaptation is injury in the chorioallantoic placenta secondary to oxidative stress. Because progressive damage accumulates in villi, placental dysfunction evolves, yielding suboptimal outcomes for mother and fetus. Therapeutic interventions to ameliorate the risk for preeclampsia and IUGR have proven elusive, since low-dose aspirin (37), calcium supplementation (30), L-arginine ingestion (36), and vitamins C and E supplementation have little, if any, benefit (5,9,14,27,29,31,32,38). There is a pressing need to identify new approaches for prophylaxis of placental dysfunction that yield a high benefit-to-risk ratio to improve pregnancy outcomes in women susceptible to pregnancy disorders.Pomegranate, the fruit of Punica granatum, contains compounds that have not only antioxidant activity but also can affect expression of multiple genes (19, 23). Pomegranate juice contains high levels of polyphenols, including ellagitannins, gallotannins, and flavonoids. This juice improves...

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Enhanced Basal Apoptosis in Cultured Term Human Cytotrophoblasts is Associated with a Higher Expression and Physical Interaction of p53 and Bak

Cited by 26 publications

References 36 publications

Essential role of p53 in trophoblastic apoptosis induced in the developing rodent placenta by treatment with a DNA-damaging agent

Essential role of p53 in trophoblastic apoptosis induced in the developing rodent placenta by treatment with a DNA-damaging agent

Two different HPV-11E6 fusion proteins trap p53 in the cytoplasm and induce apoptosis

Punicalagin, a polyphenol in pomegranate juice, downregulates p53 and attenuates hypoxia-induced apoptosis in cultured human placental syncytiotrophoblasts

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