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

The aim of our work was to study the expression of apoptotic signaling proteins and its relation to apoptosis level in neuroendocrine system of HER2/neu transgenic mice in aging. SHR mice served as controls. Bcl-2, Mcl-1, p53 and caspase-8 were demonstrated by immunohistochemistry in supraoptic (SON) and paraventricular (PVN) hypothalamic nuclei and relative content of apoptotic neurosecretory cells was determined. It was demonstrated that apoptosis regulation in different nuclei in old SHR mice was mediated by various signaling pathways: in SON, p53-independent cascade was activated, while in PVN it was p53-dependent. Overexpression of HER2/neu was shown to protect against the age-related apoptosis activation in neurosecretory centers. HER2/neu suppressed the synthesis of proapoptotic protein p53, causing the reduction of caspase-8 expression, that resulted in the increased survival of neurosecretory cells in aging.
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PMID:[Age-dependent peculiarities of apoptotic marker proteins expression in the neuroendocrine system of Her2/neu transgenic mice]. 1772 67

A ubiquitin protein ligase (E3), E3(Histone)/LASU1 (Mule/ARF-BP1/HUWE1), was recently identified that mediates ubiquitination of core histones, the Mcl-1 anti-apoptotic protein, and the p53 tumor suppressor protein. However, the expression of E3(Histone)/LASU1 remains poorly studied. Because we identified E3(Histone)/LASU1 from the testis, we explored its regulation during spermatogenesis. In the first wave of rat spermatogenesis, E3(Histone)/LASU1 mRNA and protein had peak expression at days 10 and 20, respectively, and decreased with age. Consistent with these findings, immunohistochemistry revealed that E3(Histone)/LASU1 was highly expressed in nuclei from spermatogonia to mid-pachytene spermatocytes. There was no obvious staining in spermatids, when histones are ubiquitinated and degraded. E3(Histone)/LASU1 was also expressed in other tissues. However, except in neuronal cells of the brain, expression was cytoplasmic. Thus, E3(Histone)/LASU1 may play a role in chromatin modification in early germ cells of the testis, but also has functions in other tissues.
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PMID:Regulated expression of the ubiquitin protein ligase, E3(Histone)/LASU1/Mule/ARF-BP1/HUWE1, during spermatogenesis. 1782 42

Although camptothecin (CPT) has been reported to induce apoptosis in various cancer cells, the molecular details of this regulation remain largely unknown. In this study, we demonstrate that BH3-only protein Noxa is upregulated during CPT-induced apoptosis, which is independent of p53. In addition, we show that phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is responsible for Noxa's induction. Luciferase assay and cAMP response element binding protein (CREB) knockdown experiments further demonstrate that CREB is involved in the transcriptional upregulation of Noxa. Moreover, blocking Noxa expression using specific small interfering ribonucleic acid (siRNA) significantly reduces the apoptosis in response to CPT, indicating that Noxa is an essential mediator for CPT-induced apoptosis. Interestingly, antiapoptotic Mcl-1 was also upregulated through PI3K/Akt signaling pathway upon CPT treatment. Using immunoprecipitation assay, Noxa was found to interact with Mcl-1 in the presence or absence of CPT. Knockdown of Mcl-1 expression by short hairpin ribonucleic acid (shRNA) was shown to potentiate CPT-induced apoptosis. Consistently, ectopic overexpression of Mcl-1 rescued cells from apoptosis induced by CPT. Cells coexpressing Noxa and Mcl-1 at different ratio correlates well with the extent of apoptosis, suggesting that the balance between Noxa and Mcl-1 may determine the susceptibility of HeLa cells to CPT-induced apoptosis.
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PMID:Noxa/Mcl-1 balance regulates susceptibility of cells to camptothecin-induced apoptosis. 1797 7

The orphan nuclear receptor pregnane X receptor (PXR) plays an important role in the detoxification of foreign and endogenous chemicals, including bile acids. PXR promotes bile acid elimination by activating bile acid-detoxifying enzymes and transporters. Certain bile acids are known to promote colonic carcinogenesis by inducing colon cancer cell apoptosis. However, whether and how PXR plays a role in colon cancer apoptosis has not been reported. In this study, we showed that activation of PXR by genetic (using a constitutively activated PXR) or pharmacological (using PXR agonist rifampicin) means protected the PXR-overexpressing colon cancer HCT116 cells from deoxycholic acid-induced apoptosis. Interestingly, activation of PXR also protected HCT116 cells from adriamycin-induced cell death, suggesting that the antiapoptotic effect of PXR was not bile acid specific. Moreover, the antiapoptotic effect of PXR in HCT116 cells appeared to be independent of xenobiotic enzyme regulation, because these cells had little basal and inducible expression of bile acid-detoxifying enzymes. Instead, SuperArray analysis showed that PXR-mediated deoxycholic acid resistance was associated with up-regulation of multiple antiapoptotic genes, including BAG3, BIRC2, and MCL-1, and down-regulation of proapoptotic genes, such as BAK1 and TP53/p53. Treatment with rifampicin in colon cancer LS180 cells, a cell line known to express endogenous PXR, also inhibited apoptosis. Activation of PXR in transgenic mice inhibited bile acid-induced colonic epithelial apoptosis and sensitized mice to dimethylhydrazine-induced colonic carcinogenesis, suggesting that the antiapoptotic effect of PXR is conserved in normal colon epithelium. In summary, our results have established the antiapoptotic role of PXR in both human colon cancer cells and normal mouse colon epithelium.
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PMID:The antiapoptotic role of pregnane X receptor in human colon cancer cells. 1809 95

Multiple myeloma (MM) is an incurable plasma cell malignancy that is slow-growing, and thus traditional DNA-replication directed chemotherapeutics are ineffective. We hypothesized that those agents that target RNA-directed processes would be successful in MM. To test this postulate, cordycepin, a polyadenylation inhibitor was used as a proof-of-principle towards MM cell lines. Cordycepin accumulated in MM.1S cells as its triphosphate metabolite, 3'dATP and subsequently inhibits RNA synthesis and cell growth. Cell death was via apoptosis induction and over 50% of treated cells were annexin-V positive after 48 h. As a consequence of RNA synthesis inhibition, we hypothesized that specific genes with short half-lives may be downregulated, leading to a reduction in protein. Indeed, a reduction in the transcript levels for MET, a survival gene for MM, was detected as early as 4 h and transcripts were reduced to c. 10% of control after 48 h. Interestingly, no significant change in protein levels was observed for Bcl-2, XIAP, Mcl-1 or survivin. Stabilization of p53 was not observed, and caspases-8, -9 and -3 showed activation following cordycepin treatment but were not required for cell death. Our results suggest that RNA-directed agents may be a new group of agents for the treatment of MM.
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PMID:RNA-directed agent, cordycepin, induces cell death in multiple myeloma cells. 1820 59

p53 regulates transcription of one anti-apoptotic and four pro-apoptotic members of the BCL-2 family, but nothing is known about the regulation of MCL-1, another antiapoptotic member of this family, by p53. Confocal microscopic analysis of COS1, HEK 293 and HeLa cells transfected with a p53 expression plasmid demonstrated a decrease in the signal of endogenous MCL-1 compared to neighboring non-transfected cells. Transcription regulation assays showed that the 1826 bp human MCL-1 promoter fragment was repressed up to 30-fold by wild-type p53 in a dose-dependent manner. As shown by electrophoretic mobility shift assays, Sp1 binding to the sites located in the -295 to +16 MCL-1 promoter fragment was decreased in the presence of p53. However, the MCL-1 promoter devoid of all Sp1 binding sites was still repressed by p53, albeit 2-fold weaker than the wild-type promoter. Overexpression of Sp1 reduced p53-dependent repression of the MCL-1 promoter only up to 2.2-fold. Transcription regulation assays performed with MCL-1 promoter deletion mutants showed that most of the p53 inhibitory effect was mediated by the -41 to +16 bp promoter fragment containing binding sites only for TATA-binding protein and other basal transcription factors. We propose a novel, promoter-based mechanism by which p53 down-regulates expression of the antiapoptotic MCL-1 protein.
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PMID:p53-dependent repression of the human MCL-1 gene encoding an anti-apoptotic member of the BCL-2 family: the role of Sp1 and of basic transcription factor binding sites in the MCL-1 promoter. 1820 54

2-chloroadenosine (2-CAdo) is an adenosine deaminase-resistant analogue of adenosine, widely used as an adenosine receptor agonist. This compound has been shown to induce apoptosis in several cell types either via activation of adenosine receptors or via intracellular metabolism. However, the molecular mechanisms of 2-CAdo-induced apoptosis are unclear. Here, we analyzed the effects of 2-CAdo in the leukemia cell line EHEB. 2-CAdo was found to induce apoptosis in EHEB cells, as shown by caspase-3 activation, DNA fragmentation, poly(ADP-ribose) polymerase (PARP) cleavage and phosphatidylserine exposure. Cytotoxicity of 2-CAdo was completely suppressed by 5-iodotubercidin, an adenosine kinase inhibitor, indicating that apoptosis induced by 2-CAdo was the result of its intracellular metabolism. Accordingly, we found that 2-CAdo was efficiently converted into 2-chloroATP. In parallel, a decrease of intracellular ATP concentration as well as a general inhibition of macromolecular synthesis, involving DNA, RNA and protein synthesis, was observed. Moreover, 2-CAdo induced cytochrome c release into the cytosol, indicating activation of the intrinsic pathway of apoptosis. This was found associated with a decline in Mcl-1 protein level and p53-independent. Inhibition of AMP deaminase by coformycin markedly prevented ATP depletion, and also significantly reduced 2-CAdo cytotoxicity and caspase-3 activation. In conclusion, our data show that intracellular metabolism of 2-CAdo can lead to activation of the intrinsic pathway of apoptosis and that ATP depletion, in addition to the accumulation of the triphosphate analogue, contributes to 2-CAdo-induced apoptosis.
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PMID:Mechanisms of cell death induced by 2-chloroadenosine in leukemic B-cells. 1824 82

An important feature of Parkinson's disease is the degeneration of dopaminergic neurons in the Substantia Nigra pars compacta. Paraquat (PQ) and MPTP cause the selective degeneration of these neurons in vivo, and combining PQ with maneb exacerbates that pathology. Elucidation of the cell death mechanisms involved is important to understand how multiple environmental toxins may contribute to sporadic Parkinson's disease. We recently reported that PQ induces neuronal apoptosis through Bak activation, in contrast to MPP(+), the toxic metabolite of MPTP, which relies on Bax and p53. Here we show that individually PQ and maneb activate Bak, but together they trigger Bax-dependent cell death. Focusing on mechanisms responsible for this synergy, we found that maneb+PQ increased the expression of three strong Bak inhibitors, Bfl-1, Bcl-xL and Mcl-1, and also induced Bax activators that included Bik and Bim. Those responses favor Bax-dependent MOMP and apoptosis. SiRNA knockdown of Bax and Bak confirmed that individually PQ and maneb induce Bak-dependent cell death, but together they block the Bak pathway and activate apoptosis through Bax.
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PMID:Maneb potentiates paraquat neurotoxicity by inducing key Bcl-2 family members. 1826 26

Tyrosine kinase receptor HER2/neu plays an important role in a number of processes including carcinogenesis. The oncogenic characteristics of HER2/neu are associated with its ability to affect a variety of apoptotic pathways creating, this way, an antiapoptotic environment in the cells overexpressing this protein. The aim of our work was to investigate the features of apoptosis regulation in hypothalamic neurosecretory cells of HER2/neu transgenic mice in aging. We detected the apoptosis protein expression (Bax, c-Raf) in comparison with apoptosis level and functional activity (vasopressin concentration) in neuroendocrine system. Besides, we studied the level of 17beta-estradiol in blood plasma. 17beta-estradiol is one of possible antiapoptotic factors in neurons. We show that the apoptosis of neuroendocrine cells increases in aged wild type mice, but not in HER2/neu ones. Recently we obtained that the mechanism of apoptosis suppression in transgenic mice is the block of p53-dependent apoptosis cascade, and it is the cause of caspadse-8 decrease and dysregulation of Bcl-2 and Mcl-1 antiapoptotic protein synthesis. In this study it has been shown that Bax concentration decreases and c-Raf-1 expression does not change. 17beta-estradiol does not decrease in plasma of aged transgenic mice and it is the factor, which can play a positive role in neuroendocrine cells survival. Besides, the vasopressin synthesis increases in young and old HER2 mice. These facts result in the increased survival of neurosecretory cells in old transgenic mice.
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PMID:[Apoptosis regulation in hypothalamic neurosecretory cells of HER2/neu transgenic mice in ontogenesis]. 1838 7

2-acetyl furanonaphthoquinone (FNQ) is a naturally occurring drug with enhanced toxicity versus glucose-starved tumor cells, which frequently show topoisomerase II drug resistance. Since loss of p53 tumor suppressor function or overexpression of the anti-apoptotic bcl-2 gene can decrease susceptibility to some cancer therapies, we now investigated the effect of FNQ against genetically matched C8161 melanoma cell lines transduced to express unequal levels of Bcl-2, or engineered to harbour a functional wt p53 for comparison with dominant-negative mutant p53 R175H. Cells with differing p53 genotype showed susceptibility to FNQ. However, this response was attenuated in those overexpressing mutant p53, although a brief p53 induction was early seen in FNQ-treated wt p53 cells. Cells susceptible to FNQ showed cleavage of anti-apoptotic Mcl-1, sustained activation of the c-Jun N-terminal Kinase (p-JNK), and apoptosis-associated PARP fragmentation, all of which were counteracted in bcl-2 overexpressing cells. Suppression of JNK activation with the specific inhibitor, SP600125 also prevented FNQ-mediated cell death. Our data suggests that Bcl-2, persistent JNK phosphorylation and cleavage of anti-apoptotic Mcl-1 are key events controlling susceptibility to FNQ.
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PMID:Mcl-1 cleavage and sustained phosphorylation of c-Jun-N-terminal kinase mediate melanoma apoptosis induced by 2-acetyl furanonaphthoquinone: roles of Bcl-2 and p53. 1845 32


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