UNIPROT:P04637 - FACTA Search

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

Orphan receptors that couple to G protein without known ligands are considered to relate directly to drug discovery. Here, we examine the expression of various orphan receptors in H9c2 cells during ischemic hypoxia and reoxygenation. Among orphan receptors examined, the level of G protein-coupled receptor 41 (GPR41) mRNA increases significantly, with a peak at 2 h after reoxygenation, and recovers to the control level by 3 h after reoxygenation. The level of glyceraldehyde-3-phosphate dehydrogenase mRNA used as an internal control remains almost constant. The levels of c-fos and c-jun mRNA increase significantly with ischemic hypoxia and reoxygenation. The transfection of GPR41 into H9c2 cells results in a significant decrease in cell number, with DNA fragmentation observed by in vitro and in situ assay. The amount of p53 protein increases significantly in the nuclei of cells expressing GPR41, accompanying an increase in the transcriptional activity of p53. Consistent with the activation of p53, the level of bax mRNA is significantly increased, which leads to an increase in Bax protein. Furthermore, the expression of a deletion mutant of a GPR41, which lacks the G protein binding site and shows an attenuation of intracellular phosphorylation signals to H9c2 cells, inhibits cell death and the increase in p53 protein within 24 h after reoxygenation. These observations demonstrate that GPR41 is a novel receptor that activates p53 leading to apoptosis during reoxygenation after ischemic hypoxia in H9c2 cells. We have designated GPR41 as the hypoxia-induced apoptosis receptor, HIA-R.
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PMID:Orphan G protein-coupled receptor, GPR41, induces apoptosis via a p53/Bax pathway during ischemic hypoxia and reoxygenation. 1133 18

Huntington's disease (HD) is a hereditary neurodegenerative condition caused by a characteristic mutation in the huntingtin (htt) gene. This gene was identified in 1993. Both the mitochondria and the nucleus play an important role in HD pathology. However, the precise molecular mechanisms remain unclear. A key strategy for understanding HD pathology is to identify signaling cascades initiated by mutant Htt that lead to neuronal cell death and dysfunction. Apoptotic stress induces greater mitochondrial depolarization in HD lymphoblasts than in control subjects. This leads to overactivation of caspase-3, which is capable of cleaving htt. Truncated forms of Htt, which are similar to the caspase-cleaved products in size, exist in the nucleus of HD patient and animal model brains. We hypothesize that caspases, which are activated by mitochondrial depolarization, play a role in producing truncated forms of Htt, which accumulate in the nucleus. Truncated forms of mutant Htt that accumulate in the nucleus are toxic to cells. There is growing evidence that truncated forms of mutant Htt in the nucleus influence gene transcription by binding to proteins such as CREB binding protein (CBP) response element binding protein binding protein, N-COR, glyceraldehyde-3-phosphate dehydrogenase, and p53. p53 regulates the transcription of various mitochondrial proteins which may underlie the mitochondrial abnormalities, especially the vulnerability to mitochondrial depolarization, seen in HD tissues. Taken together, we hypothesize a noxious signaling cascade between the mitochondria and the nucleus, initiated by mutant Htt, which may underlie HD pathology.
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PMID:Mechanisms for neuronal cell death and dysfunction in Huntington's disease: pathological cross-talk between the nucleus and the mitochondria? 1146 59

The small GTPase Rab2 immunolocalizes to vesicular tubular clusters (VTCs) that function as transport complexes carrying cargo between the endoplasmic reticulum and the Golgi complex. Our previous studies showed that Rab2 promotes vesicle formation from VTCs and that the released vesicles are enriched in beta-coat protein, protein kinase C iota/lambda (PKCiota/lambda), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and the recycling protein p53/gp58. Because PKCiota/lambda kinase activity was necessary for vesicle formation, a search was initiated to identify the substrate(s) that potentiate Rab2 function within VTCs. In this study, we found that PKCiota/lambda phosphorylates GAPDH. Moreover, GAPDH interacts directly with the PKCiota/lambda regulatory domain. Based on numerous observations that show (beta-COP) GAPDH associates with cytoskeletal elements, we examined the role of phospho-GAPDH in promoting microtubule (MT) binding to membrane. Using a quantitative microsomal binding assay, we found that membrane association of beta-tubulin was dependent on phospho-GAPDH and was blocked by reagents that interfere with Rab2-dependent GAPDH membrane recruitment or with PKCiota/lambda kinase activity. Furthermore, normal rat kidney cells transfected with a constitutively activated form of Rab2 (Q65L) or with our anti-GAPDH polyclonal antibody displayed a dramatic change in MT organization. These combined results suggest that Rab2 stimulated PKCiota/lambda and GAPDH recruitment to VTCs, and the subsequent PKCiota/lambda phosphorylation of GAPDH ultimately influences MT dynamics in the early secretory pathway.
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PMID:Glyceraldehyde-3-phosphate dehydrogenase is phosphorylated by protein kinase Ciota /lambda and plays a role in microtubule dynamics in the early secretory pathway. 1172 94

Over the past several years, we have developed a number of novel aliphatic propargylamine-related compounds. These can be divided into 14 main chemical families. These families have been shown to possess members that selectively and stereochemically (i.e. R-enantiomer) rescue neurons from p53-dependent apoptosis in vitro. In contrast, no rescue has been observed by the enantiomers of the opposite configuration or in p53-independent apoptosis. In vivo, several compounds have been shown to possess neural rescue properties in models of unilateral hypoxia/ischaemia, focal ischaemia, facial nerve axotomy, pmn mice, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse and MPTP non-human primate. Our prototype compound, R-2HMP, has been shown to be metabolised in a manner analogous to that of R-deprenyl but devoid of amphetaminergic metabolites. These compounds have been shown to be active through an interaction with the same binding site as R-deprenyl and CGP 3466. This site is suggested to be the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH).
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PMID:Aliphatic propargylamines as symptomatic and neuroprotective treatments for neurodegenerative diseases. 1220 Jan 97

Controversy has surrounded a role for apoptosis in the loss of neurons in Parkinson's disease (PD). Although a variety of evidence has supported an apoptotic contribution to PD neuronal loss particularly in the nigra, two factors have weighed against general acceptance: (1) limitations in the use of in situ 3' end labeling techniques to demonstrate nuclear DNA cleavage; and (2) the insistence that a specific set of nuclear morphological features be present before apoptotic death could be declared. We first review the molecular events that underlie apoptotic nuclear degradation and the literature regarding the unreliability of 3' DNA end labeling as a marker of apoptotic nuclear degradation. Recent findings regarding the multiple caspase-dependent or caspase-independent signaling pathways that mediate apoptotic nuclear degradation and determine the morphological features of apoptotic nuclear degradation are presented. The evidence shows that a single nuclear morphology is not sufficient to identify apoptosis and that a cytochrome c, pro-caspase 9, and caspase 3 pathways is operative in PD nigral apoptosis. BAX-dependent increases in mitochondrial membrane permeability are responsible for the release of mitochondrial factors that signal for apoptotic degradation, and increased BAX levels have been found in a subset of PD nigral neurons. Studies using immunocytochemistry in PD postmortem nigra have begun to define the premitochondrial apoptosis signaling pathways in the disease. Two, possibly interdependent, pathways have been uncovered: (1) a p53-glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-BAX pathway; and (2) FAS receptor-FADD-caspase 8-BAX pathway. Based on the above, it seems unlikely that apoptosis does not contribute to PD neuronal loss, and the definition of the premitochondrial signaling pathways may allow for the development and testing of an apoptosis-based PD therapy.
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PMID:Apoptosis in Parkinson's disease: signals for neuronal degradation. 1266 99

Various risk factors have been implicated in the causation of cervical cancer including human papillomavirus (HPV), the early genes (E6 and E7 ) of which encode the main transforming proteins. Studies have suggested that steroid hormones may enhance the expression of these genes leading to loss of p53 gene-mediated cell apoptosis. A total of 120 cervical tissue samples were obtained from patients with proven cervical cancer. Patients who used depo-medroxyprogesterone acetate steroid contraception were recruited as part of the steroid arm. Only HPV DNA type 16 samples were used for the study. Controls included three cell lines (CaSki, SiHa, & C33A) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as an internal housekeeping gene. Of 120 patients, there were 111 patients with HPV type 16 identified. Of this number, RNA was present in 63 samples. There were 30 women (30/63) who used steroid contraception. In relation to patients who used contraception, HPV 16 E6 gene expression was present in 79% (n = 23) and 88% (n = 30) of steroid users compared to nonusers, respectively. In total there were 25 patients (40%) with expression of the HPV 16 E6*I gene and 30 patients with expression of the E6*II gene. There were 57% of steroid users (n = 17) who had expression of the E6*I/E6*II gene, compared to 52% (n = 17) of nonusers (P = 0.800). From a molecular level, this study does not confirm the role of injectable progesterones in cervical carcinogenesis.
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PMID:The interaction between steroid hormones, human papillomavirus type 16, E6 oncogene expression, and cervical cancer. 1467 21

To understand the cellular functions of HDM2, we attempted to identify novel HDM2-interacting proteins by proteomic analysis. Along with previously identified interactions with the ribosomal proteins, our analysis reveals interactions of HDM2 with the ribosomal translation elongation factor EF1alpha, 40S ribosomal protein S20, tubulins, glyceraldehyde 3-phosphate dehydrogenase, and a proteolysis-inducing factor dermicidin in the absence of tumor suppressor p53. Because a CTCL tumor antigen HD-CL-08 has high degree of homology with EF1alpha, we confirmed interaction of HDM2 with EF1alpha by immunoprecipitation and Western blot analysis in transformed as well as near normal diploid cells. Endogenous HDM2- EF1alpha complex was detected in cancer cells overexpressing HDM2, suggesting a possible role of this interaction in HDM2-mediated oncogenesis. Consistent with their interaction, colocalization of HDM2 and EF1alpha can be detected in the cytoplasm of normal or transformed cells. Amino acid residues 1-58 and 221-325 of HDM2 were found to be essential for its interaction with EF1alpha, suggesting that the interaction is independent of its other ribosomal interacting proteins L5, L11, and L23. Overexpression of HDM2 did not affect translation. Because EF1alpha has been implicated in DNA replication and severing of microtubules, interaction of HDM2 with EF1alpha may signify a p53-independent cell growth regulatory role of HDM2.
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PMID:HDM2-binding partners: interaction with translation elongation factor EF1alpha. 1737 42

Purpose. MDM2 is an oncogene whose protein product may promote tumorigenesis by blocking wild-type p53 tumor suppressor mediated G (0)/G(1) cell cycle arrest, thereby inhibiting repair of damaged DNA prior to cell division. While MDM2 DNA amplification is frequently observed in human sarcoma, the mechanisms linking this amplification to MDM2 oncoprotein over-production as well as its functional significance have not been well characterized in patients with soft tissue sarcoma.Methods. A tissue bank of resected soft tissue sarcomas and autologous normal tissues was assembled; all specimens were snap frozen within 15 min of resection. DNA and RNA were extracted from tissues using isoamyl alcohol and phenol chloroform extraction methods, respectively; cell lysates were prepared using PBSTDS lysis buffer. DNA and mRNA were confirmed as being non-degraded and were then examined for MDM2 DNA amplification (Southern blots) and mRNA over-expression (Northern blots) using actin (DNA) and glyceraldehyde-3-phosphate dehydrogenase (mRNA) as loading controls. The MDM2 protein was examined on Western blots using the MDM2-specific monoclonal antibody IF2 (Oncogene Science, Inc). The presence of p53 DNA and expression of p53 mRNA was examined by rehybridizing the Southern and Northern filters using a p53-specific cDNA probe.Results. Soft tissue sarcomas and autologous normal tissues were screened for MDM2 DNA amplification, which was detected in 10 of 30 tumors screened. After screening, there was sufficient biomaterials from six specimens for subsequent Northern and Western analysis to see whether MDM2 gene amplification correlated with over-expression of MDM2 mRNA and MDM2 protein. In addition, we examined whether other mechanisms may lead to over-expression of the MDM2 oncoprotein. Several possible mechanisms of MDM2 oncoprotein over-expression were identified. These most commonly included MDM2 DNA amplification, MDM2 mRNA over-expression and MDM2 oncoprotein over-expression. However, some soft tissue sarcoma patient specimens had no evidence of MDM2 mRNA over-expression yet had MDM2 oncoprotein over-production in the tumor relative to autologous normal tissue, implying possible post-transcriptional regulation. Of functional relevance, MDM2 oncoprotein over-production by tumors was associated with large decreases in the percentage of cells in the (0)/G(1) cell cycle interface compared with autologous normal tissue cells.Discussion. It is likely that there are multiple mechanisms underlying human soft tissue sarcoma MDM2 oncoprotein over-production. Consequently, strategies that decrease MDM2 over-production, such as transcriptional repression to inhibit MDM2 promoter activity or RNA antisense approaches, may ultimately offer the best therapeutic efficacy.
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PMID:Enhanced MDM2 Oncoprotein Expression in Soft Tissue Sarcoma: Several Possible Regulatory Mechanisms. 1852 Nov 97

Besides its role in glycolysis, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) initiates a cell death cascade. Diverse apoptotic stimuli activate inducible nitric oxide synthase (iNOS) or neuronal NOS (nNOS), with the generated nitric oxide (NO) S-nitrosylating GAPDH, abolishing its catalytic activity and conferring on it the ability to bind to Siah1, an E3-ubiquitin-ligase with a nuclear localization signal (NLS). The GAPDH-Siah1 protein complex, in turn, translocates to the nucleus and mediates cell death; these processes are blocked by procedures that interfere with GAPDH-Siah1 binding. Nuclear events induced by GAPDH to kill cells have been obscure. Here we show that nuclear GAPDH is acetylated at Lys 160 by the acetyltransferase p300/CREB binding protein (CBP) through direct protein interaction, which in turn stimulates the acetylation and catalytic activity of p300/CBP. Consequently, downstream targets of p300/CBP, such as p53 (Refs 10,11,12,13,14,15), are activated and cause cell death. A dominant-negative mutant GAPDH with the substitution of Lys 160 to Arg (GAPDH-K160R) prevents activation of p300/CBP, blocks induction of apoptotic genes and decreases cell death. Our findings reveal a pathway in which NO-induced nuclear GAPDH mediates cell death through p300/CBP.
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PMID:Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis. 1855 33

Tumour suppressor protein p53 prevents cancer development through various mechanisms, including the induction of apoptosis. We demonstrated that acute leukaemia, myeloblastic (AML) and lymphoblastic (ALL), is associated with significantly elevated levels of p53 and Bax mRNA in leukaemic cells. Regarding ALL, significantly elevated levels of Bcl-xL mRNA may explain the relative resistance of ALL cells to p53-dependent apoptosis. Altered alternative processing of Bcl-x and myeloid cell leukaemia-1 (MCL1) primary transcripts were observed in the case of AML and AML and ALL, respectively. We assumed that increased glyceraldehyde-3-phosphate dehydrogenase (gapdh) transcription and decreased MCL1s mRNA were not fully responsible for the dysregulation of p53-dependent apoptosis in the case of AML. In addition, transcription of hsp70.1 and Bcl-2 producing anti-apoptotic proteins was not affected in acute leukaemia.
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PMID:Transcription of genes of p53-dependent apoptosis in acute leukaemia. 1902 Jul 83

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