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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since human trophoblast undergoes extensive proliferation and exhibits invasive growth comparable to that of a malignant tumour, human placenta at various different stages of gestation was investigated immunohistochemically with the monoclonal antibody Ab-6 for expression of the p53 tumour suppressor gene. p53 protein was detected in the nuclei of a few trophoblastic cells, almost all belonging to the cytotrophoblast and only very few to the syncytiotrophoblast, in nearly all specimens investigated (first trimester 10/10, second trimester 5/5, third trimester 4/5). First trimester trophoblast exhibited increased expression of p53 protein in the juxtastromal areas of cytotrophoblast cell islands and columns, that is, in areas where high proliferative activity and increased expression of the epidermal growth factor receptor have been described in the literature. Staining was also occasionally seen in trophoblast invading the myometrium. It is most likely that immunohistochemically detectable expression of p53 protein in the trophoblast is due not to mutation of the gene, as in malignant tumours, but rather to up-regulation of the p53 tumour suppressor gene, which could be a mechanism for controlling trophoblast proliferation.
Placenta 1995 Jan
PMID:Expression of the p53 tumour suppressor gene in human placenta: an immunohistochemical study. 771 22

Proliferation and differentiation of villous trophoblast during placental development, from an early stage to full-term, were investigated in routinely fixed and processed tissues, by means of the immunocytochemical localization of the cell cycle-related proto-oncogene c-myc and the p53 and retinoblastoma susceptibility (Rb) tumour-suppressor gene products. The proliferative activity of the trophoblast was determined using an antibody against proliferating cell nuclear antigen (PCNA) which stains all proliferating cells in paraffin-embedded tissues. Diffuse nuclear immunoreactivity for PCNA, c-myc and Rb gene products was a consistent finding in early cytotrophoblast; c-myc product expression was also detectable in both layers of mid-gestation trophoblast. Only scattered cytotrophoblastic nuclei of early gestational placenta displayed immunostaining for p53 gene product. In full-term placenta c-myc expression was undetectable while Rb gene product and PCNA immunoreactivity declined markedly. These results indicate that the expression of the above genes is spatio-temporally regulated during placental development. A potential involvement of the oncosuppressor gene products p53 and Rb in the control of trophoblastic proliferation and of c-myc in the control of both the proliferative and differentiation pathways of trophoblastic cells is suggested.
Placenta 1994 Jun
PMID:C-myc and tumour suppressor gene product expression in developing and term human trophoblast. 793 96

This study investigates the extent of apoptosis in complete hydatidiform mole (CHM), using an in situ 3'-end DNA labelling (TUNEL) technique on formalin-fixed and paraffin-embedded sections. The sections were also immunostained with antibodies to p53, Bax and Bcl-2 proteins. In 10 normal placenta cases and 15 CHM cases, the apoptotic index was <1 and 2-4 per cent, respectively. The labelled trophoblastic cells possessed pyknotic nuclei and densely eosinophilic cytoplasm which corresponded well to the so-called apoptotic bodies by light and electron microscopy. The p53 positive reaction was restricted to the nuclei of cytotrophoblasts and intermediate trophoblasts, while the syncytiotrophoblasts showed only rare immunolocalization. Strong p53 expression was seen most often in cytotrophoblasts of CHM (>30 per cent of nuclei) which also showed a higher apoptosis index, while cytotrophoblasts in normal placentae were weakly and focally labelled (<10 per cent of nuclei). There were statistical differences between normal and CHM cases (P<0.05). Bcl-2 accumulation, on the other hand, was observed predominantly in syncytiotrophoblasts of normal placentae, and cytotrophoblasts and intermediate trophoblasts did not express Bcl-2 in all cases. Interestingly, syncytiotrophoblasts were found to be negative for Bax protein and positive in cytotrophoblast, which is consistent with the function of the protein in conveying increased apoptosis susceptibility to this cell population. The results show that the level of apoptosis correlates with the histological type of the gestational trophoblasts, and apoptosis index is higher in cytotrophoblasts in CHM. The fact that p53 quantitative expression and an increase in the Bax/Bcl-2 ratio were also observed in CHM suggested that they may contribute partly to the high level of apoptosis.
Placenta
PMID:p53, Bax and Bcl-2 expression, and apoptosis in gestational trophoblast of complete hydatidiform mole. 969 56

In order to understand the involvement of the p53 tumour suppressor gene in the pathogenesis of gestational trophoblastic disease (GTD), we investigated its genetic status, protein expression and its role in apoptosis in samples of complete and partial hydatidiform mole as compared with those of normal placenta. Direct sequencing of polymerase chain reaction (PCR) products of the coding and non-coding regions of the p53 gene demonstrated no mutations in any of the studied samples. Immunohistochemical studies revealed increased expression of the p53 protein predominantly in the nuclei of villous cytotrophoblasts. This over-expression of p53 was found in all samples of complete mole, in 50 per cent of partial mole samples and in about 30 per cent of normal placenta cases, although no significant difference in the staining intensity and pattern was observed. An in situ detection of DNA nicking (TUNEL) staining, demonstrating apoptosis, was also detected predominantly in villous cytotrophoblasts and in stromal areas. The per centage of apoptotic cells in all studied samples, determined by flow cytometry, demonstrated a significant increase in apoptotic cells in samples of complete and partial hydatidiform mole compared with those of normal placenta (P< 0.0003 and P< 0.004, respectively). In conclusion, the current study may provide a possible explanation to the pathogenesis of GTD, probably associated with extensive p53-dependent apoptosis to modulate excessive trophoblastic proliferation.
Placenta 2000 Jan
PMID:Expression of the p53 gene and apoptosis in gestational trophoblastic disease. 1069 52

Trophoblast giant cells in the rodent placenta form the outermost layer of the extraembryonic compartment, establish direct contact with maternal cells, and produce a number of pregnancy-specific cytokine hormones. Giant cells differentiate from proliferative trophoblasts as they exit the cell cycle and enter a genome-amplifying endocycle, a process we show involves decreased expression of the G1 checkpoint proteins p53 and Rb. Although p53 mRNA levels are unchanged in proliferative compared to differentiated trophoblasts, p53 protein levels are markedly reduced in giant cells. Forced expression of wild type p53 in trophoblasts inhibits differentiation, and expression of a dominant negative p53 peptide stimulates differentiation. Consistent with the loss of p53 protein, differentiated trophoblasts become resistant to apoptosis-inducing agents. Decreased expression of Rb is also detected during differentiation, and overexpression of Rb in trophoblasts inhibits giant cell differentiation. Although an increase in E2F activity would be expected with the loss of Rb, what is observed is an overall decrease in E2F DNA-binding complexes, a shift to new complexes, and a decrease in E2F-dependent gene expression in differentiating trophoblasts. Overall, these results indicate that the combination of a decrease in p53 and Rb represents a functionally important part of the transition of trophoblasts from a proliferative cell cycle to an endocycle in the giant cell differentiation programme.
Placenta 2004 Jan
PMID:Differentiation of placental trophoblast giant cells requires downregulation of p53 and Rb. 1501 36

Maternal cigarette smoking is known to disrupt placental growth and function. The polyaromatic hydrocarbon benzo[a]pyrene (BaP) is a major toxicant in cigarette smoke that has been shown to alter placental cell function. This study compared the effects of the benzo[a]pyrene (BaP) with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the prototype ligand for the aryl hydrocarbon (Ah) receptor, on proliferation and cell cycle progression in the human trophoblastic JEG-3 cell line. BaP, but not TCDD, significantly inhibited proliferation in a dose-dependent manner characterized by G2/M cell cycle phase arrest. No evidence of apoptosis was detected following BaP or TCDD exposure. Immunocytochemistry and Western blot analysis showed that BaP induced expression of nuclear p21CIP1 protein, the major inhibitor of cyclin-dependent kinases. In contrast, CDK1 expression, the main G2 cyclin-dependent kinase, was significantly reduced by 50% with a shift in localization from the nucleus to cytoplasm. Although BaP had no effect on total cellular p53 levels, phosphorylation of p53 at serine 15 (p53 ser-15phos) was markedly increased. The presence of Wortmannin, an inhibitor of PI-3 kinases, decreased BaP-induced p53 ser-15phos, as did the presence of the antioxidant vitamin E. In addition, vitamin E suppressed BaP-induced G2/M arrest without altering the level of induced CYP1A1 protein. Thus, the anti-proliferative effect of BaP involves activation of a p53-dependent pathway involving cell cycle arrest at G2/M, providing evidence of oxidative stress and activation of a DNA damage response pathway in JEG-3 cells.
Placenta 2005 Apr
PMID:Benzo[a]pyrene, but not 2,3,7,8-TCDD, induces G2/M cell cycle arrest, p21CIP1 and p53 phosphorylation in human choriocarcinoma JEG-3 cells: a distinct signaling pathway. 1583 74

Gestational trophoblastic diseases are a group of interrelated diseases of trophoblastic tissue that include partial hydatidiform mole, complete hydatidiform mole, invasive mole, choriocarcinoma, and placental site trophoblastic tumor. P63 is a p53 homologue that, in normal placentas, is expressed in the cytotrophoblast cells. The role of p63 in gestational trophoblastic diseases, however, merits further investigation. Immunohistochemistry with the p63 antibody (clone 4A4) was performed in formalin-fixed paraffin-embedded samples of hydropic abortion (n=10), partial hydatidiform mole (n=12), complete hydatidiform mole (n=12) and choriocarcinoma (n=5). P63 expression was quantitatively assessed as 0 (no stained cells), + (less than 10% positive cells), ++ (10-50% positive cells), and +++ (more than 50% positive cells). The intensity was scored as 0 (absence), + (weak), ++ (moderate), or +++ (strong). Statistical analysis was carried out by the Fisher test. In contrast to the other diagnoses, none of the choriocarcinomas analyzed exhibited p63-positive cells. There was no difference in distribution of p63 positive cells between hydropic abortion, partial hydatidiform mole, and complete hydatidiform mole. Concerning the intensity of immunostaining, there was difference only between partial hydatidiform mole and complete hydatidiform mole. According to our results, p63 might be useful to differentiate a choriocarcinoma from other gestational trophoblastic diseases. Besides, since the intensity of p63 expression was much stronger in partial hydatidiform mole and complete hydatidiform mole than in hydropic abortion, this feature may be helpful in distinguishing these two diagnoses in challenging cases.
Placenta
PMID:P63 expression in hydropic abortion and gestational trophoblastic diseases. 1602 31

We tested the hypothesis that the expression levels of p53 and the pro-apoptotic mediators from the Bcl-2 family are higher in cytotrophoblasts, when compared to cultures with abundant syncytiotrophoblasts. Cytotrophoblasts isolated from normal term human placentas were cultured in Dulbecco's Modified Eagle medium (DMEM) for 24 h, when the cytotrophoblast phenotype predominates, in DMEM for 72 h, when the syncytiotrophoblast phenotype predominates, or in Ham's-Waymouth medium or DMEM with 1.5% dimethylsulfoxide, each of which maintains the cytotrophoblast phenotype through 72 h of culture. Apoptosis was assessed by detection of cleavage products of poly-ADP-ribose polymerase, by expression of cleaved cytokeratin 18 intermediate filaments, and by assessment of caspase-3 activity. Independent of time in culture, cytotrophoblasts showed higher levels of apoptosis compared to syncytiotrophoblasts. Cytotrophoblasts also expressed a 2-fold higher level of p53, a 2-fold lower level of 60 kDa Mdm-2 protein, a 2-fold higher level of Bak, but no differences in the expression of 90 kDa Mdm-2, Bcl-2, Bcl-X(L), Mcl-1, Bax, Bad, and Bad phosphorylated at the serine(112), serine(136), or serine(155) sites, compared to the syncytiotrophoblasts. Using co-immunoprecipitation, we demonstrated a greater degree of Bak-p53 interaction in cytotrophoblasts than in syncytiotrophoblasts. We also detected Bak-Mcl-1 interaction that was no different between the two phenotypes. Among the proteins studied, enhanced p53 activity, differential Bak expression, and Bak-p53 interactions may contribute to the higher level of constitutive apoptosis in cultures of cytotrophoblasts compared to syncytiotrophoblasts.
Placenta
PMID:Enhanced basal apoptosis in cultured term human cytotrophoblasts is associated with a higher expression and physical interaction of p53 and Bak. 1637 85

Placental apoptosis is exaggerated in pre-eclampsia and cytotrophoblast proliferation is enhanced. This imbalance may be a primary pathogenic event, whereby excessive syncytiotrophoblast apoptosis counters cytotrophoblast fusion, promoting the liberation of syncytial material which perturbs the maternal vascular endothelium. We have previously shown that primary trophoblasts and explant cultured villous fragments from pre-eclamptic pregnancies elicit greater levels of terminal differentiation and apoptosis. This review considers current opinions in trophoblast cell turnover in normal pregnancy and pre-eclampsia. In the context of other findings, this review highlights: (i) the disparity in expression of pro-apoptotic transcription factor p53 in the syncytiotrophoblast in pre-eclampsia, (ii) the importance of reactive oxygen species and hypoxia in initiating villous trophoblast apoptosis and (iii) the concept that aberrant intervillous haemodynamics, as opposed to oxygen per se, initiates excessive syncytiotrophoblast shedding. Finally, therapeutic ways of restoring the syncytiotrophoblast in pre-eclampsia and preventing excessive placental apoptosis are considered, including a role for mitotic manipulators and growth factor replacement strategies.
Placenta 2007 Apr
PMID:Gabor Than Award Lecture 2006: pre-eclampsia and villous trophoblast turnover: perspectives and possibilities. 1737 2

Pre-eclampsia (PE) and intrauterine growth restriction (IUGR) are associated with aberrant cell turnover, including increased apoptosis, in placental villous trophoblast. The increased apoptosis is associated with exaggerated expression of p53, which promotes cell cycle arrest or apoptosis via downstream proteins such as p21 or Bax. These changes in apoptosis and p53 expression are purported to result from exposure to altered oxygen tension. Using a model of villous trophoblast turnover, we examined the effect of 20%, 6% and 1% ambient oxygen (O(2)) on apoptosis, necrosis, proliferation and expression of p53 and related regulators of cell turnover, compared to both fresh tissue. Altered O(2) tension exerted an effect on cell turnover in cultured term villous tissue: cytotrophoblast proliferation was increased by culture in 20% O(2) and reduced in 1% O(2) (median proliferative index: fresh tissue=0.32%, 20% O(2)=0.9%, 6% O(2)=0.28%, 1% O(2)=0.07%). Apoptosis was increased in all culture environments, but was significantly enhanced by culture in 1% O(2) (median apoptotic index: fresh tissue=0.64%, 20% O(2)=2.96%, 6% O(2)=3.81%, 1% O(2)=9.2%). Necrotic cell death was also increased by culture in 1% O(2) compared to 6% and 20% O(2). The expression of p53, p21 and Mdm2 in both cytotrophoblast and stromal cells was increased following culture in 1% O(2). There was no alteration in the expression of Bax or Bcl-2. This study provides evidence that p53 is elevated in trophoblast following exposure to hypoxia. The potential role of the p53-pathway in the control of cell turnover in villous trophoblast and the regulation of p53 by altered O(2) tension merits further investigation.
Placenta 2008 Feb
PMID:Effects of oxygen on cell turnover and expression of regulators of apoptosis in human placental trophoblast. 1815 42


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