Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epigallocatechin-3-gallate (EGCG) has been shown to have anticarcinogenic effects in in vitro and in vivo models, and this effect is mediated at least in part by its ability to induce apoptosis in cancer cells without affecting normal cells. It has been recognized that estrogen receptor (ER)-dependent breast cancers generally have a better prognosis and are often responsive to antiestrogen therapy; however, ER-independent breast cancers are more aggressive and unresponsive to antiestrogens. Using the MDA-MB-468 human breast cancer cell line as an in vitro model of ER-negative breast cancers, we found that treatment of EGCG resulted in dose-dependent (5-80 microg/mL) and time-dependent (24-72 hours) inhibition of cellular proliferation (15-100%) and cell viability (3-78%) in MDA-MB-468 cells. Decrease in cell viability was associated with the induction of apoptosis (18-66%) which was analyzed by DNA ladder assay, fluorescence staining, and flow cytometry. Induction of apoptosis by EGCG could be corroborated to the increased expression of tumor suppressor protein p53 and its phosphorylation at Ser 15 residue. EGCG decreased the expression of antiapoptotic protein Bcl-2 but increased proapoptotic protein Bax in these cells. The increased ratio of Bax/Bcl-2 proteins after EGCG treatment may have resulted in increased release of cytochrome c from mitochondria into cytosols, increased expression of Apaf-1, and activation of caspase-3 and poly(ADP-ribose) polymerase, which may lead to apoptosis in MDA-MB-468 cells. Together, the results of this study provide evidence that EGCG possesses anticarcinogenic effect against ER-negative breast cancer cells and thus provide the molecular basis for the future development of EGCG as a novel and pharmacologically safe chemopreventive agent for breast cancer prevention.
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PMID:Epigallocatechin-3-gallate induces apoptosis in estrogen receptor-negative human breast carcinoma cells via modulation in protein expression of p53 and Bax and caspase-3 activation. 1565 56

Grape seed proanthocyanidins (GSP) have been shown to inhibit skin chemical carcinogenesis and photocarcinogenesis in mice. The mechanisms responsible for the anticarcinogenic effects of GSP are not clearly understood. Here, we report that treatment of JB6 C141 cells (a well-developed cell culture model for studying tumor promotion in keratinocytes) and p53+/+ fibroblasts with GSP resulted in a dose-dependent induction of apoptosis. GSP-induced (20-80 g/ml) apoptosis was observed by using immunofluorescence (27-90% apoptosis) and flow cytometry (18-87% apoptosis). The induction of apoptosis by GSP was p53-dependent because it occurred mainly in cells expressing wild-type p53 (p53+/+; 15-80%) to a much greater extent than in p53-deficient cells (p53-/-; 6-20%). GSP-induced apoptosis in JB6 C141 cells was associated with increased expression of the tumor-suppressor protein, p53, and its phosphorylation at Ser15. The antiapoptotic proteins, Bcl-2 and Bcl-xl, were downregulated by GSP, whereas the expression of the pro-apoptotic protein, Bax, and the levels of cytochrome c release, Apaf-1, caspase-9, and cleaved caspase 3 (p19 and p17) were markedly increased in JB6 C141 cells. The downregulation of Bcl-2 and upregulation of Bax were also observed in wild-type p53 (p53+/+) fibroblasts but was not observed in their p53-deficient counterparts. These data clearly demonstrate that GSP-induced apoptosis is p53-dependent and mediated through the Bcl-2, Bax, and caspase 3 pathways.
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PMID:Grape seed proanthocyanidins induce apoptosis through p53, Bax, and caspase 3 pathways. 1572 Aug 15

Although a number of p53 target genes have been identified, the mechanisms of p53-dependent activities that determine cellular survival or death are still not fully understood. Here we report isolation of a novel p53 target gene, designated p53-inducible cell-survival factor (p53CSV). p53CSV contains a p53-binding site within its second exon and the reduction of expression by small interfering RNA enhanced apoptosis, whereas overexpression protected cells from apoptosis caused by DNA damage. p53CSV is induced significantly when cells have a low level of genotoxic stresses, but not when DNA damage is severe. p53CSV can modulate apoptotic pathways through interaction with Hsp70 that probably inhibits activity of apoptosis protease activating factor-1. Our results imply that under specific conditions of stress, p53 regulates transcription of p53CSV and that p53CSV is one of the important players in the p53-mediated cell survival.
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PMID:p53CSV, a novel p53-inducible gene involved in the p53-dependent cell-survival pathway. 1573 3

Hepatitis C virus (HCV) core protein has multifunctional activities. We have previously reported that the core protein of HCV immortalizes primary human hepatocytes, which may relate to multistage hepatocarcinogenic events. These immortalized human hepatocytes (IHH) served as a model to study the mechanism of HCV core protein-mediated cell growth regulation. Inhibition of core protein expression in earlier stages after hepatocyte immortalization leads to the induction of apoptosis. Here, we have observed that introduction of antisense core (AS-Core) sequences for inhibition of core protein expression enhanced the expression of E2F1 and p53 levels in early passage IHH. Inhibition of core protein expression also altered the expression level of Bcl-2 family proteins, displaying an increase of the proapoptotic Bax and a decrease in the level of the anti-apoptotic Bcl-xL proteins. These alterations, however, did not result in the release of cytochrome c from the mitochondria. Apaf-1 is frequently deregulated under various pathologic conditions, and examination of AS-Core-expressing apoptotic cells indicated a significant increase in the level of Apaf-1, which coincided with caspase-9 activation. Knockdown of Apaf-1 or the transcriptional regulatory proteins, E2F1 or p53, by small interfering RNA (siRNA) duplexes inhibited the activation of caspase-9 and enhanced cell viability in AS-Core-expressing cells. These findings may contribute to the understanding of the pathophysiology of HCV core protein-mediated hepatocyte growth regulation and disease progression.
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PMID:Inhibition of hepatitis C virus core protein expression in immortalized human hepatocytes induces cytochrome c-independent increase in Apaf-1 and caspase-9 activation for cell death. 1589 61

A time course study was performed to reveal the sequence of histopathology after Trichinella spiralis or T. pseudospiralis infection in mice. A cyst was formed in the former case by about 18 days post infection and prominent myopathy was restricted within the cyst. In the latter case, however, no typical cyst was formed, and myopathy spread diffusely over the infected muscle tissues occupying half the area of muscle sections. An electron microscope observation revealed that the disintegration of muscle cells was delayed in T. pseudospiralis infection than in T. spiralis infection. Quantitative reverse transcription polymerase chain reaction (RT-PCR) showed that apoptosis-related genes were expressed for a longer term in muscles infected with T. pseudospiralis than in those with T. spiralis, although the same spectrum of genes are mobilized. Examined apoptosis-related genes included tumor suppressor genes p53, p53; mouse double minute 2, MDM2; cyclin-dependent kinase inhibitor p21 (WAF1), p21(waf) ; Bcl-2 associated protein X, BAX; apoptotic protease activating factor 1, Apaf-1; Caspase 9 and serine/ threonine protein kinase, PKB. Micro-dissection of the infected muscle tissue and subsequent RT-PCR confirmed that the expressions of these genes are restricted to tissue with myopathy. Thus, the expression of the apoptosis-related genes correlated with continuous and diffuse myopathy caused by T. pseudospiralis infection.
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PMID:Trichinella pseudospiralis infection is characterized by more continuous and diffuse myopathy than T. spiralis infection. 1594 11

Difficulties in evaluation of trichloroethylene (TRI)-induced toxicity in humans and extrapolation of data from laboratory animals to humans are due to the existence of multiple target organs, multiple metabolic pathways, sex-, species-, and strain-dependent differences in both metabolism and susceptibility to toxicity, and the lack or minimal amount of human data for many target organs. The use of human tissue for mechanistic studies is thus distinctly advantageous. The kidneys are one target organ for TRI and metabolism by the glutathione (GSH) conjugation pathway is responsible for nephrotoxicity. The GSH conjugate is processed further to produce the cysteine conjugate, S-(1,2-dichlorovinyl)-l-cysteine (DCVC), which is the penultimate nephrotoxic species. Confluent, primary cultures of human proximal tubular (hPT) cells were used as the model system. Although cells in log-phase growth, which are undergoing more rapid DNA synthesis, would give lower LD(50) values, confluent cells more closely mimic the in vivo proximal tubule. DCVC caused cellular necrosis only at relatively high doses (>100 muM) and long incubation times (>24 h). In contrast, both apoptosis and enhanced cellular proliferation occurred at relatively low doses (10-100 muM) and early incubation times (2-8 h). These responses were associated with prominent changes in expression of several proteins that regulate apoptosis (Bcl-2, Bax, Apaf-1, Caspase-9 cleavage, PARP cleavage) and cellular growth, differentiation and stress response (p53, Hsp27, NF-kappaB). Effects on p53 and Hsp27 implicate function of protein kinase C, the mitogen activated protein kinase pathway, and the cytoskeleton. The precise pattern of expression of these and other proteins can thus serve as molecular markers for TRI exposure and effect in human kidney.
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PMID:Molecular markers of trichloroethylene-induced toxicity in human kidney cells. 1596 4

Apaf-1 is important for tumor suppression and drug resistance because it plays a central role in DNA damage-induced apoptosis. Inactivation of the Apaf-1 gene is implicated in disease progression and chemoresistance of some malignancies. In this study, we attempted to clarify the role of Apaf-1 in leukemogenesis. Apaf-1 mRNA levels were below the detection limit or very low in 5 of 20 human leukemia cell lines (25%) and 5 of 12 primary acute myeloblastic leukemia cells (42%). There were no gross structural abnormalities in the Apaf-1 gene in these samples. Expression of factors regulating Apaf-1 transcription, such as E2F-1, p53, and Sp-1, did not differ between Apaf-1-positive and Apaf-1-negative cells. Methylation of CpG in the region between +87 and +128 of the Apaf-1 gene was almost exclusively observed in Apaf-1-defective cell lines. Treatment of these cells with 5-aza-2'-deoxycytidine, a specific inhibitor of DNA methylation, restored the expression of Apaf-1. Furthermore, we showed that the region between +87 and +128 could act as a repressor element by recruiting corepressors such as methylated DNA-binding domain 2 and histone deacetylase 1 upon methylation. Overexpression of Dnmt1, a mammalian maintenance DNA methyltransferase, was associated with Apaf-1 gene methylation. DNAs from Dnmt1-overexpressing cells were more resistant to digestion with methylation-sensitive enzyme HpaII than those from cells with low Dnmt1 expression, suggesting that Dnmt1 mediates aberrant methylation of multiple genes. In conclusion, methylation silencing is a mechanism of the inactivation of Apaf-1 in acute leukemia, and Dnmt1 overexpression may underlie hypermethylation of the Apaf-1 gene.
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PMID:Methylation silencing of the Apaf-1 gene in acute leukemia. 1597 51

Abnormal activation of CXCR 4 during inflammatory/infectious states may lead to neuronal dysfunction or damage. The major goal of this study was to determine the coupling of CXCR 4 to p53-dependent survival pathways in primary neurons. Neurons were stimulated with the HIV envelope protein gp120(IIIB) or the endogenous CXCR 4 agonist, SDF-1 alpha. We found that gp120 stimulates p53 activity and induces expression of the p53 pro-apoptotic target Apaf-1 in cultured neurons. Inhibition of CXCR 4 by AMD 3100 abrogates the effect of gp120 on both p53 and Apaf-1. Moreover, gp120 neurotoxicity is markedly reduced by the p53-inhibitor, pifithrin-alpha. The viral protein also regulates p53 phosphorylation and expression of other p53-responsive genes, such as MDM 2 and p21. Conversely, SDF-1 alpha, which can promote neuronal survival, increases p53 acetylation and p21 expression in neurons. Thus, the stimulation of different p53 targets could be instrumental in determining the outcome of CXCR 4 activation on neuronal survival in neuro-inflammatory disorders.
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PMID:Regulation of neuronal P53 activity by CXCR 4. 1600 38

Cyclin-dependent kinase 5 (Cdk5) is a member of the cyclin-dependent kinase family that is mostly seen in neurons, does not vary with cell cycle, and is activated in many neurodegenerative disorders and other non-neuronal pathologies, but its relationship to non-neuronal apoptosis is not understood, nor is the control of the activation of Cdk5 by its activators. The most widely studied activator of Cdk5, p35, is cleaved to p25 by calpain, an event that has been linked with activation of Cdk5 and neuronal death. Here we report that calpain-mediated Cdk5/p25 activation accompanies non-neuronal as well as neuronal cell death, suggesting that the p35/calpain/p25/Cdk5 activation sequence is a general feature of cell death. We further demonstrate that Cdk5 can be activated in the absence of p53, Apaf-1, caspase-9, and -3 during cell death, indicating that its activation relates more to cell death than to a specific pathway of apoptosis.
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PMID:p53, Apaf-1, caspase-3, and -9 are dispensable for Cdk5 activation during cell death. 1602 Nov 78

Aging of skeletal muscle is often accompanied by muscle atrophy and it appears that apoptosis plays an important role in this process. The detailed mechanism(s) is not completely understood, however. In this study, we examined expression of the apoptosis regulatory proteins as well as the heat shock proteins, which have been shown to modulate the apoptotic process in certain cell types, in order to more completely elucidate apoptotic signaling in aged skeletal muscle. To more specifically identify alterations that are likely to be the result of aging, we compared 16-month-old middle-aged (MD) and 29-month-old senescent (SE) male Fischer 344 x Brown Norway rats in our study. Our results show that the degree of DNA laddering was higher in SE compared to MD rats. Using total tissue homogenates we examined the level of expression of several apoptosis-related proteins in two categories: mitochondria-associated proteins and caspases. Of the mitochondria-associated proteins, the levels of p53 showed a significant increase in SE compared to MD rats. There was also a significant increase in the expression of Bax, Bcl-2 and Apaf-1 in SE rats over that of MD rats; cytochrome c and AIF levels remained unchanged, however. Regarding the caspases, there were increases in the levels of pro-caspases-12 and -7 and cleaved caspase-9, although the levels of pro- and cleaved caspase-3 as well as cleaved caspase-12 remained unchanged. Furthermore, our results showed significant increases in HSP27, HSP60, and the inducible HSP70. These data show that in rat skeletal muscle increased apoptosis occurs between middle-age and senescence, indicating an aging-related increase in apoptosis in skeletal muscle. The involvement of different apoptotic pathways in the aging process is suggested by the selective alterations in the apoptosis regulatory proteins. The increased expression of the HSPs suggests a relationship between HSPs and the aging-related apoptotic process.
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PMID:Age-related alterations in expression of apoptosis regulatory proteins and heat shock proteins in rat skeletal muscle. 1613 96


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