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

The disruption of cell cycle regulation is associated with developmental abnormalities and tumorigenesis. The SV40 large T antigen (Tag) interferes with cell cycle control by interacting with the pRb family and p53. Mice carrying a transgene composed of the whey acidic protein (WAP) gene promoter and the Tag coding sequence express Tag during pregnancy and are unable to nurse their young. Tag expression induced apoptosis in mammary epithelial cells during late pregnancy. At least 5% of mammary epithelial cells were undergoing apoptosis at any one time. In contrast, less than 0.2% of mammary epithelial cells in nontransgenic littermates was undergoing apoptosis. Apoptosis in Tag mice was associated with increased steady-state RNA levels of bax and bcl-xL + S, with a relative increase in bcl-xs expression. Since p53 was sequestered by Tag, it is likely that p53-independent mechanisms precipitated apoptosis. The Tag-expressing mammary alveolar cells that did not undergo apoptosis continued to differentiate through late pregnancy, as measured by the sequential activation of milk protein gene expression. However, milk protein production, processing, and secretion was impaired, resulting in lactation failure.
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PMID:Expression of a viral oncoprotein during mammary gland development alters cell fate and function: induction of p53-independent apoptosis is followed by impaired milk protein production in surviving cells. 878 28

Mammary gland involution is a physiological process that follows lactation and results in the rapid disappearance of the entire lobulo-alveolar compartment. Coincident with the onset of involution, milk protein gene expression ceases and alveolar cells undergo programmed cell death. In mammary epithelial tissue culture cells in vitro, both p53-dependent and p53-independent apoptosis pathways have been identified. We investigated whether p53 induces apoptosis during mammary gland involution in vivo and participates in tissue remodeling. Toward this end, we examined the process of involution in the presence and absence of functional p53 in mouse models: wild-type, transgenic mice that express SV40 T-antigen specifically in mammary tissue during pregnancy; and mice that carry nonfunctional p53 alleles in their germ line. Mammary gland whole-mount and histological analyses revealed that involution and remodeling, with the concomitant disappearance of the lobulo-alveolar structures, proceeded normally in the absence of functional p53. In addition, the absence of functional p53 did not alter the involution related pattern of bax (death inducer) gene expression or the ratio of RNAs encoding bcl-xs (death inducer) to bcl-xL (survival inducer).
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PMID:Apoptosis and remodeling of mammary gland tissue during involution proceeds through p53-independent pathways. 878 29

The proto-oncogene c-myc has been implicated in both cellular proliferation and apoptosis, and we have shown that overexpression of c-myc can induce polycystic kidney disease in transgenic mice. To elucidate the molecular and cellular defects underlying cystogenesis, we have investigated the potential roles of cell proliferation and apoptosis as they relate to c-myc and modulators of c-myc function in human autosomal dominant polycystic kidney disease (ADPKD). Renal c-myc expression was consistently elevated, up to 15-fold, in ADPKD. High levels of c-myc expression correlated with 10- to 100-fold increased proliferation index in cystic epithelium. Interestingly, steady-state levels of bcl-2 mRNA were also increased up to 20-fold and Bcl-2 protein was markedly elevated. In contrast, the expression of bax and p53 was virtually unchanged. However, apoptosis was consistently and significantly increased in ADPKD kidneys, unchecked by high levels of Bcl-2. Together with proliferation, apoptosis may thus represent a general mechanism for cyst growth and tissue remodeling. We conclude that both epithelial cell proliferation and apoptosis required for normal kidney homeostasis are deregulated in ADPKD, recapitulating the renal developmental program. Furthermore, abnormal expression of proto-oncogenes regulating these processes is an important mediator of cystogenesis in human ADPKD.
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PMID:Dysregulation of cellular proliferation and apoptosis mediates human autosomal dominant polycystic kidney disease (ADPKD). 880 89

The cooked meat mutagen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) produces tumors at multiple sites in the F344 rat, including adenocarcinomas of the colon. In the present study, the development of IQ-induced colorectal tumors was shown to be accompanied by the progressive inhibition of programmed cell death. This was associated with increased expression of the antiapoptosis protein Bcl-2 and decreased expression of bax, a known activator of apoptosis. Carcinomas bearing high levels of bcl-2 expression exhibited low levels of p53, the tumor suppressor protein that in some circumstances has been shown to down-regulate bcl-2. Because they lack mutations in the genes commonly associated with increased cell proliferation (APC, Ki-ras, and p53) and show no evidence of microsatellite instability, IQ-induced colon tumors might arise via the deregulation of bcl-2 expression, leading to inhibition of programmed cell death.
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PMID:Inhibition of apoptosis in colon tumors induced in the rat by 2-amino-3-methylimidazo[4,5-f]quinoline. 881 12

Programmed cell death in mammary tissue was studied during natural weaning in lactating mice and after litter removal or milk stasis. All treatments stimulated mammary apoptosis, indicating that this process is an integral part of the tissue's involution after lactation. Induction of apoptosis was slower in natural weaning than after litter removal but occurred earlier when mice were concurrently pregnant during natural weaning. Ipsilateral induction of apoptosis by milk stasis in teat-sealed glands indicates that cell death is under local (i.e., intramammary) as well as endocrine regulation. Apoptosis detected by DNA laddering was associated with changes in expression of p53 and bax, two genes implicated in the regulation of cell death, and was accompanied by structural degeneration characteristic of mammary involution. Reciprocal changes in stromelysin mRNA, and that of its inhibitor TIMP-2, suggested that this structural reorganisation was the result of coordinated changes in gene expression favouring proteolysis of the extracellular matrix.
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PMID:Programmed cell death during mammary tissue involution induced by weaning, litter removal, and milk stasis. 881 10

Histiocytic necrotizing lymphadenitis, also called Kikuchi-Fujimoto (KF) disease, is a benign disorder characterized histologically by paracortical necrotic foci surrounded by histiocytic aggregates. We analysed affected lymph node tissues from 34 patients with the disease in an attempt to elucidate its histogenesis. The 'necrotizing' cells showed typical apoptotic changes, including cell shrinkage and condensed and fragmented nuclei. Apoptotic bodies with a peculiar ultrastructure were demonstrated, and DNA fragmentation was detected in these cells by in situ end labelling. Immunostaining for the apoptosis-regulating proteins bcl-2, bax, c-myc and p53 failed to show their involvement in KF disease. However, perforin, a killer cell-specific cytolytic protein essential for provoking apoptosis in target cells, was found to be expressed abundantly by the infiltrating cells, which were thought to be cytotoxic T-lymphocytes. Perforin-expressing cells were present in the apoptotic foci of 28 of the 34 patients (82.4%). Virtually no cells containing perforin granules were present in non-pathological regions, lymph node tissues from control subjects with reactive or tuberculous lymphadenitis or those from patients with KF disease with negligible apoptosis. Therefore, the 'necrosis' associated with KF disease appears to be attributable to trans apoptotic death of the killer cell target in the affected nodes. We propose that KF disease should be called apoptotic lymphadenitis.
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PMID:Involvement of cell-mediated killing in apoptosis in histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease). 883 19

More than half of human cancers contain p53 mutations. Structural analyses of p53-DNA interactions indicate that hot spots of p53 mutation are often either involved in direct contact with target DNA or those that maintain specific conformation of p53. One significant consequence of the loss of wild type p53 function is inhibition of apoptosis, which may be through the inability of mutant p53 to transcriptionally activate bax gene expression. Quantitative correlation among ultraviolet-induced p53 mutations of keratocytes, inhibition of apoptosis and the development of squamous cell cancer of the skin further suggest a central role of inhibited apoptosis between p53 mutations and tumorigenesis. Hypoxia-mediated selection for p53 mutant cells with diminished apoptotic potential in solid tumors may account for the high prevalence of p53 mutations in human cancers. Our increasing understanding of the role of p53 mutations and apoptosis in human cancers has also provided some insights into strategies for anticancer therapy. Studies reconstituting the wild-type p53 through gene therapy have been encouraging. More importantly, further elucidation of the mechanisms of therapy-induced p53-independent apoptosis in cancer cells will facilitate the development of more efficient, less toxic anticancer therapy.
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PMID:p53, apoptosis and human cancers. 884 Jul 52

In all normal tissues, cell proliferation and cell death are balanced. The physiology of normal cell death, which has become generally known as apoptosis or programmed cell death, has been intensely investigated in recent years. In this review the cell biology and biochemistry of apoptosis are discussed. Although apoptotic cells can be morphologically recognized, characteristic molecular features such as internucleosomal DNA fragmentation, and histochemical techniques such as in situ end labeling, facilitate the recognition of apoptosis. Many of the genes involved in the regulation of apoptosis, which include cell growth associated genes such as c-myc and p53, have been identified. It has become clear that the bcl-genes (more explicitly bcl-2 and bax) are important apoptosis regulators. The details of the mechanism of programmed cell death are, however, not completely unraveled. It has become clear that apoptosis plays an important role in organ and tissue development during embryogenesis. Examples are the morphogenesis of limbs from limb buds, the development of the central nervous system and the maturation of the hematopoietic and lymphatic systems. Hormonal regulation of cells and tissues is also partly executed through apoptosis. In a variety of disease apoptosis plays a role. In cancer, apoptosis is a crucial feature, and in the resolution of inflammatory reactions, apoptosis is essential. In neurodegenerative diseases, dysregulation of the cell death programme may play a role. Further elucidation of the role of apoptosis in these diseases may lead to new possibilities for treatment.
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PMID:Apoptosis: pathophysiology of programmed cell death. 888 Aug 68

P53 is of key importance for the protection of an organism against carcinogenesis. P53 performs this function by the regulation of several cellular processes, the most important of which are apoptosis and cell-cycle progression. P53 controls these processes most likely through the transcriptional regulation of target genes, such as those for p21waf1 and bax. Since p53 is involved in the regulation of these distinct processes, the protein should be able to respond quickly to environmental changes. P53 is a phosphoprotein phosphorylated on multiple sites by a variety of kinases. The two main phosphorylation domains are the N and the C terminus. The N-terminal part contains the transcription-regulatory domain of p53, while the C-terminal domain controls the specific DNA binding by p53. Here we present an overview of the kinases known to phosphorylate p53 and the effects of phosphorylation on biochemical and biological functions. The picture that emerges shows that phosphorylation of p53 on specific sites can modulate the activity of the protein, either by affecting its abundance, the affinity for its DNA-consensus sequence or the activity of the transcription-activation domain. Furthermore, the kinases involved are downstream targets of different inducers, such as DNA-damage/stress inducers and mitogens, giving the cell the opportunity to respond to distinct extracellular stimuli via modulation of p53 activity.
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PMID:How phosphorylation regulates the activity of p53. 891 92

The E6 gene of tumor-associated types of human papillomaviruses codes for a functional antagonist of p53. Overexpression of E6 from heterologous promoters can block p53-mediated cellular responses to DNA damage, such as transcriptional stimulation of p53 target genes and cell-cycle arrest in G1. In contrast, genotoxic treatment of HPV-positive cancer cells, which express the E6 gene from chromosomally integrated viral copies, results in increased expression of the p53 target gene p21WAF1 and, in several cell lines, induction of G1 arrest. In the present study, we show that treatment with genotoxic agents, such as mitomycin C and cisplatin, leads to strong repression of viral E6/E7 oncogene expression in HPV16- and HPV18-positive cervical carcinoma cell lines. Kinetic analyses revealed that reduction of E6/E7 expression was not a prerequisite for induction of p21WAF1. We furthermore found that the apoptosis-promoting bax gene could be induced by genotoxic stress in some, but not all, HPV-positive cancer cell lines. Treatment with DNA-damaging agents eventually resulted in apoptotic cell death of HPV-positive cancer cells, irrespective of their capacity to induce the p53 target gene bax. These results support the notion that HPV-positive cancer cells can exhibit intact cellular responses to genotoxic stress, which may involve p53-dependent and -independent biochemical pathways. The ability of HPV-positive cancer cells to induce apoptotic cell death in response to DNA damage could provide a molecular explanation for the therapeutic effects of genotoxic agents in the treatment of cervical cancer.
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PMID:Cellular responses of HPV-positive cancer cells to genotoxic anti-cancer agents: repression of E6/E7-oncogene expression and induction of apoptosis. 894 23


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