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)

Classical cytotoxic therapy has been minimally useful in the treatment of hepatocellular carcinoma. In an effort to develop a new approach to the treatment of this neoplasm, we have investigated the signal transduction pathways regulating the growth of human hepatoma cells. In the data reported here, cyclic AMP (cAMP), a negative growth regulator for many cells of epithelial origin, induced G1 synchronization and apoptosis in the HepG2 human hepatoma cell line. The effects of cAMP on the components of the G1/S transition were analyzed. There was no detectable effect of two different cAMP analogs, 8-bromo cAMP or dibutyryl cAMP on the level of the D-type cyclins, cyclin E, cyclin-dependent kinase 2, cyclin-dependent kinase 4, p53, or the cyclin-dependent kinase inhibitors p21 or p27. In contrast, the cAMP analogs induced a dramatic downregulation of cyclin A protein, cyclin A messenger RNA, and cyclin A-dependent kinase activity. Cyclin A-dependent kinase has been shown to be required for the G1-S transition. Furthermore, cyclin A deregulation has been implicated in the pathogenesis of hepatocellular carcinoma. The data reported here suggest a novel signal transduction-based approach to hepatoma therapy.
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PMID:Cyclic AMP induces inhibition of cyclin A expression and growth arrest in human hepatoma cells. 1020 5

Immunohistochemical analysis of the expression of the autosomal apoptosis regulator genes, BAX, bcl-2, p53, and cyclic-AMP responsive element modulator (CREM) in testis biopsies from infertile men demonstrated that BAX, bcl-2, and p53 immunoreactivity was absent irrespective of seminiferous tubule histology. In contrast, cell-specific CREM immunoreactivity in round spermatids, with complete absence of CREM in patient biopsies showing spermatocyte maturation arrest and Sertoli cell only, was evident, suggesting a possible role of autosomal genes in the regulation of apoptosis in human spermatogenesis regulation.
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PMID:The role of autosomal cell apoptosis regulator genes in human spermatogenesis. 1048 69

Interactions between glutamatergic mechanisms mediated by receptors of the ionotropic and metabotropic classes in the central nervous system are complex and incompletely understood. To explore the consequences of these interactions on excitotoxicity, we examined the influence of group II and group III selective metabotropic glutamate receptor agonists on the N-methyl-D-aspartate-induced apoptotic destruction of GABAergic neurons in rat striatum. The intrastriatal administration of a group III metabotropic glutamate receptor agonist (amino-4-phosphonobutyric acid, 900-1800 nmol), but not of a group II agonist [(2S,1'S,2'S)-(carboxycyclopropyl)glycine, 100-1800 nmol] produced internucleosomal DNA fragmentation. Similarly, amino-4-phosphonobutyric acid (600 nmol) but not (2S,1'S,2'S)-(carboxycyclopropyl)glycine (100-1800 nmol) destroyed some striatal neurons as indicated by a loss of D1 dopamine receptors and 67,000 mol. wt glutamate decarboxylase (glutamate decarboxylase-67) messenger RNA. On the other hand, the intensity of internucleosomal DNA fragmentation induced by N-methyl-D aspartate (150 nmol) was substantially decreased by the intrastriatal co-administration of either (2S,1'S,2'S)-(carboxycyclopropyl)glycine or amino-4-phosphonobutyric acid (100-600 nmol). Both (2S, 1'S,2'S)-(carboxycyclopropyl)glycine and amino-4-phosphonobutyric acid also reduced the N-methyl-D-aspartate-induced loss of striatal D1 dopamine receptors by 67% and 68% (both P < 0.001), and glutamate decarboxylase-67 messenger RNA by 68% and 61%, respectively. Furthermore, both (2S,1'S,2'S)-(carboxycyclopropyl)glycine and amino-4-phosphonobutyric acid also attenuated the N-methyl-D-aspartate-induced decline in striatal IKB-alpha protein levels by 62% and 37%, as well as the increase in nuclear transcription factor nuclear factor-kappaB binding activity by 135% and 94% (both P < 0.001), and the subsequent rise in p53 and c-Myc protein levels. These results suggest that stimulation of cyclic-AMP-linked metabotropic glutamate receptors inhibits ionotropic glutamate receptor-mediated activation of apoptotic cascades involving IkappaB-alpha degradation and nuclear factor-kappaB nuclear translocation, as well as p53 and c-Myc induction. Certain selective metabotropic glutamate receptor agonists might thus find utility as adjuncts to N-methyl-D-aspartate antagonists in the protection against the neurotoxicity initiated by excessive ionotropic glutamate receptor stimulation.
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PMID:Co-stimulation of cyclic-AMP-linked metabotropic glutamate receptors in rat striatum attenuates excitotoxin-induced nuclear factor-kappaB activation and apoptosis. 1062 54

The role of phosphorylation in the regulation of p53 protein function is little understood. We have addressed the role of protein kinase C (PKC) in the phosphorylation. Exposure to the protein kinase inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H7), increased the phosphorylation of wild type p53 protein, whereas exposure to the tumor promoter phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), decreased it in vivo following 3 hours incubation with mouse epidermal JB6 cells. Exposure to the c-AMP dependent protein kinase (PKA) activator, forskolin, did not decrease the phosphorylation of p53 protein. In the transient transfection/luciferase reporter transactivation assay, H7 modestly increased the mouse double minute (MDM) 2 reporter transactivation activity of p53 protein after 24 hours treatment, and TPA completely blocked it. These results suggest that the accelerated phosphorylation of wild type p53 protein is inversely related to PKC activation, and that p53 phosphorylation may have some relation to transcription factor function.
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PMID:Phosphorylation status and function of P53 are inversely related to protein kinase C activation. 1076 27

CREB binding protein (CBP) is a 270-kDa nuclear protein required for activated transcription of a large number of cellular genes. Although CBP was originally discovered through its interaction with phosphorylated CREB (pCREB), it is utilized by a multitude of cellular transcription factors and viral oncoproteins. Both CREB and the tumor suppressor p53 have been shown to directly interact with the KIX domain of CBP. Although coactivator competition is an emerging theme in transcriptional regulation, we have made the fortuitous observation that protein kinase A-phosphorylated CREB strongly enhances p53 association with KIX. Phosphorylated CREB also facilitates interaction of a p53 mutant, defective for KIX binding, indicating that CREB functions in a novel way to bridge p53 and the coactivator. This is accomplished through direct interaction between the bZIP domain of CREB and the amino terminus of p53; a protein-protein interaction that is also detected in vivo. Consistent with our biochemical observations, we show that stimulation of the intracellular cyclic AMP (cAMP) pathway, which leads to CREB phosphorylation, strongly enhances both the transcriptional activation and apoptotic properties of p53. We propose that phosphorylated CREB mediates recruitment of CBP to p53-responsive promoters through direct interaction with p53. These observations provide evidence for a novel pathway that integrates cAMP signaling and p53 transcriptional activity.
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PMID:p53 recruitment of CREB binding protein mediated through phosphorylated CREB: a novel pathway of tumor suppressor regulation. 1084 10

In transformed human glial cells, abnormalities of the p53 gene and altered expression of glial-specific properties (GSPs) have been observed. We therefore investigated whether (i) expression of the altered p53 protein is involved in the reduced expression of GSPs; and (ii) expression of the wild-type p53 (wt-p53) gene leads to induction of GSPs. We first determined that the p53 gene is mutated in human glioblastoma U-373MG cells. In these cells, and in human T-98G glioblastoma cells reported to possess a mutated p53 (m-p53) gene, nuclear m-p53 expression was intense while GSP expression was low in the same cell as revealed by double labelling immunocytochemistry. Conversely, glial fibrillary acidic protein (GFAP) and glutamate synthase (GS) were expressed in cells devoid of nuclear m-p53 immnunoreactivity. Therefore, a mutually exclusive relationship exists between the cytoplasmic GSPs and nuclear m-p53. Upon treatment with retinoic acid (RA) and dibutyryl cyclic AMP (dbcAMP), overall GSP staining were increased concomitant with suppression of nuclear m-p53. Their mutually exclusive expression pattern was maintained suggesting a functional relationship. This is supported by the observation of a similar mutually exclusive expression pattern for p53 and GSPs in pathologic specimens of human glioblastoma tissues. We then explored the role of the wt-p53 gene in the induction of GSPs using a wt-p53 tetracycline-regulated conditional expression system in human LN-Z308 glioblastoma cells. These cells normally express no p53 and no appreciable levels of GS or GFAP. Induced expression of wt-p53 lead to induction of GSP. These observations are consistent with the hypotheses that (i) nuclear m-p53 expression and cytoplasmic expression of GFAP and GS are inversely correlated, and (ii) expression of the wt-p53 gene leads to the expression of GSPs.
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PMID:Alteration in p53 modulates glial proteins in human glial tumour cells. 1110 Aug 17

The tumor suppressor protein p53 regulates various cellular responses to DNA damage and plays a significant role in DNA repair. The nuclear p300/cyclic AMP-responsive element binding (CREB)-binding protein (CBP) proteins act as coactivators in supporting the transcription function of p53. We examined the role of the human homologue of yeast Rad23 protein A (hHR23A), one of the two human homologues of the Saccharomyces cerevisiae nucleotide excision repair gene product Rad23, in the p300/CBP-associated regulation of p53 activity. Overexpression of wild-type hHR23A inhibits the p53 transcriptional activity and results in a decreased steady-state protein level of cellular p53. The inhibitory effect of hHR23A can be overcome by the concomitant expression of p300, CBP, and p300 segments harboring C/H1 domain and neutralized by the coexpression of HIV accessory protein Vpr, which binds COOH terminus of hHR23A/B. Additionally, hHR23A was shown to interact in vitro and in vivo with p300 segments harboring C/H1 domain. These studies provide evidence for the involvement of hHR23A in the regulation of p53 activity through p300/CBP. Although the precise direct role of hHR23 proteins in regulation of p53 and DNA repair remains to be elucidated, our data suggest that the interaction between hHR23A and p300/CBP has important implications in cross-talk between the p53 pathway and DNA repair.
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PMID:Human homologue of yeast Rad23 protein A interacts with p300/cyclic AMP-responsive element binding (CREB)-binding protein to down-regulate transcriptional activity of p53. 1119 99

The human AP endonuclease (Ape1 or ref-1) DNA base excision repair (BER) enzyme is a multifunctional protein that has an impact on a wide variety of important cellular functions including oxidative signaling, transcription factor regulation, and cell cycle control. It acts on mutagenic AP (baseless) sites in DNA as a critical member of the DNA BER repair pathway. Moreover, Ape1/ref-1 stimulates the DNA-binding activity of transcription factors (Fos-Jun, nuclear factor-kappaB, Myb, ATF/cyclic AMP-responsive element binding protein family, HIF-1alpha, HLF, PAX, and p53) through a redox mechanism and thus represents a novel component of signal transduction processes that regulate eukaryotic gene expression. Ape1/ref-1 has also been shown to be closely linked to apoptosis associated with thioredoxin, and altered levels of Ape1/ref-1 have been found in some cancers. In a pilot study, we have examined Ape1/ref-1 expression by immunohistochemistry in sections of germ cell tumors (GCTs) from 10 patients with testicular cancer of various histologies including seminomas, yolk sac tumors, and malignant teratomas. Ape1/ref-1 was expressed at relatively high levels in the tumor cells of nearly all sections. We hypothesized that elevated expression of Ape1/ref-1 is responsible in part for the resistance to therapeutic agents. To answer this hypothesis, we overexpressed the Ape1/ref-1 cDNA in the GCT cell line NT2/D1 using retroviral gene transduction with the vector LAPESN. Using an oligonucleotide cleavage assay and immunohistochemistry to assess Ape1/ref-1 repair activity and expression, respectively, we found that the repair activity and relative Ape1/ref-1 expression in GCT cell lines are directly related. NT2/D1 cells transduced with Ape1/ref-1 exhibited 2-fold higher AP endonuclease activity in the oligonucleotide cleavage assay, and this was reflected in a 2-3-fold increase in protection against bleomycin. Lesser protection was observed with gamma-irradiation. We conclude that: (a) Ape1/ref-1 is expressed at relatively high levels in some GCTs; (b) elevated expression of Ape1/ref-1 in testicular cancer cell lines results in resistance to certain therapeutic agents; and (c) Ape1/ref-1 expression in GCT cell lines determined by immunohistochemistry and repair activity assays parallels the level of protection from bleomycin. We further hypothesize that elevated Ape1/ref-1 levels observed in human testicular cancer may be related to their relative resistance to therapy and may serve as a diagnostic marker for refractory disease. To our knowledge, this is the first example of overexpressing Ape1/ref-1 in a mammalian system resulting in enhanced protection to DNA-damaging agents.
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PMID:Altered expression of Ape1/ref-1 in germ cell tumors and overexpression in NT2 cells confers resistance to bleomycin and radiation. 1128 Jul 90

Small DNA tumor viruses such as simian virus 40 (SV40) and polyomavirus (Py) take advantage of host cell proteins to transcribe and replicate their DNA. Interactions between the viral T antigens and host proteins result in cell transformation and tumor induction. Large T antigen of SV40 interacts with p53, pRb/p107/p130 family members, and the cyclic AMP-responsive element-binding protein (CREB)-binding protein (CBP)/p300. Py large T antigen is known to interact only with pRb and p300 among these proteins. Here we report that Py large T binds to CBP in vivo and in vitro. In co-transfection assays, Py large T inhibits the co-activation functions of CBP/p300 in CREB-mediated transactivation but not in NF-kappa B-mediated transactivation. p53 appears not to be involved in the functions of CREB-mediated transactivation and is not essential for large T:CBP interaction. Mutations introduced into a region of Py large T with homology to adenovirus E1A and SV40 large T prevent binding to the co-activators. These mutant large T antigens fail to inhibit CREB-mediated transactivation. The CBP/p300-binding Py mutants are able to transform established rat embryo fibroblasts but are restricted in their ability to induce tumors in the newborn mouse, indicating that interaction of large T with the co-activators may be essential for virus replication and spread in the intact host.
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PMID:Binding of p300/CBP co-activators by polyoma large T antigen. 1143 28

AMP-activated protein kinase (AMP-kinase) modulates many metabolic processes in response to fluctuations in cellular energy status. Although most of its known targets are metabolic enzymes, it has been proposed that AMP-kinase might also regulate gene expression. Here we demonstrate that the transcriptional coactivator p300 is a substrate of AMP-kinase. Phosphorylation of p300 at serine 89 by AMP-kinase dramatically reduced its interaction, in vitro and in vivo, with the nuclear receptors peroxisome proliferator-activated receptor gamma, thyroid receptor, retinoic acid receptor, and retinoid X receptor, but did not affect its interaction with the non-nuclear receptor transcription factors E1a, p53, or GATA4. These findings indicate that the AMP-kinase signaling pathway selectively modulates a subset of p300 activities and represent the first example of a transcriptional component regulated by AMP-kinase. Our results suggest a direct link between cellular energy metabolism and gene expression.
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PMID:Regulation of transcription by AMP-activated protein kinase: phosphorylation of p300 blocks its interaction with nuclear receptors. 1151 99


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