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)

Cell extracts of the thermophile Clostridium thermohydrosulfuricum catalyzed the phosphorylation by [gamma-32P]ATP of several endogenous proteins with Mrs between 13,000 and 100,000. Serine and tyrosine were the main acceptors. Distinct substrate proteins were found in the soluble (e.g., proteins p66, p63, and p53 of Mrs 66,000, 63,000, and 53,000, respectively) and particulate (p76 and p30) fractions, both of which contained protein kinase and phosphatase activity. The soluble fraction suppressed the phosphorylation of particulate proteins and contained a protein kinase inhibitor. Phosphorylation of p53 was promoted by 10 microM fructose 1,6-bisphosphate or glucose 1,6-bisphosphate and suppressed by hexose monophosphates, whereas p30 and p13 were suppressed by 5 microM brain (but not spinach) calmodulin. Polyamines, including the "odd" polyamines characteristic of thermophiles, modulated the labeling of most of the phosphoproteins. Apart from p66, all the proteins labeled in vitro were also rapidly labeled in intact cells by 32Pi. Several proteins strongly labeled in vivo were labeled slowly or not at all in vitro.
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PMID:Phosphorylation of proteins in Clostridium thermohydrosulfuricum. 241 9

To study the effects of acute ethanol on regenerating rat liver, the mRNA transcript levels of growth suppressor genes (prohibitin, TGF beta-1 and p53) were measured by Northern blot analysis during the G0, G1, and early S phases of compensatory growth after 70% partial hepatectomy (PH) in adult male rats. Selected animals were gavaged with either ethanol (3 g/kg) or glucose and underwent PH 1 h later. Other animals were either sham operated or underwent PH without gavage. Prohibitin and p53 transcripts were increased in relative abundance (as measured by an increase in band intensity) near the G1/S boundary (8-12 h post-PH) following both glucose and ethanol gavage. A transient increase in prohibitin transcripts at 0.5-1 h post-PH was found to be characteristic of glucose and nongavaged rats. Ethanol gavage significantly increased the relative abundance of prohibitin transcripts at 0.5-2 h post-PH. An increase in the TGF beta-1 transcripts at 4 h post-PH was found in the glucose and nongavaged rats. Ethanol gavage resulted in variable TGF beta-1 transcript expression near hepatectomy (0 h); however, mean differences were not statistically significant. Sham operation had no effect on the mRNA transcripts of the selected genes during the time periods sampled. These results and previous work suggest that the mitoinhibitory effects of acute ethanol exposure may occur via modulation of growth suppressor and proto-oncogene expression.
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PMID:Acute ethanol and selected growth suppressor transcripts in regenerating rat liver. 754 33

The pathophysiology of mammosomatotroph adenomas remains unclear. We studied a mammosomatotroph adenoma removed from an 8-year old boy with a 5-year history of growth acceleration and acromegalic gigantism at presentation. Elevated basal GH (mean 28 micrograms/l) and PRL (mean 120 micrograms/l) plasma levels were observed, as well as paradoxical responses of GH to L-dopa, TRH and oral glucose administration; PRL was reduced by L-dopa and slightly increased by TRH; GHRH stimulated release of both GH and PRL. Two operations were required to remove the very large tumour and the patient was treated with bromocriptine before the second. Hormonal secretion by tumour explants in culture was evaluated under basal conditions and after stimulation or inhibition. High levels of GH and PRL were secreted for up to 24 days. Furthermore, GHRH and TRH caused a dose-related stimulation of both hormones, while somatostatin and dopamine were effective in suppressing either basal or stimulated hormone release only at very high (microM) concentrations. Intracellular events were studied by determination of the guanosine triphosphate binding (G) protein levels and adenylate cyclase (AC) activity in the tumour tissue. Before bromocriptine treatment, AC activity was very high in the tumour and could be further stimulated by various agents; very high levels of the AC-stimulatory G protein alpha subunit Gs alpha and very low amounts of the AC-inhibiting G protein alpha subunit Gi3 alpha and of the phospholipase C-stimulating G protein alpha subunit Gq alpha were found in the tumour. After bromocriptine, baseline AC activity was normalized and could no longer be stimulated; Gs alpha and Gi3 alpha levels were unchanged while those of Gq alpha were normalized. Screening of tumour DNA after amplification by polymerase chain reaction followed by single-strand conformational polymorphism analysis did not reveal any mutations in the hot spots of G protein alpha subunits (alpha s, alpha i2, alpha o2 and alpha 11) genes or in the H-ras and p53 genes. Gs alpha and GH transcription factor-1 (pit-1) expression were evaluated by amplification of cDNA. While the mRNA expression of pit-1 decreased after bromocriptine treatment, that of Gs alpha increased. These data suggest the possibility of an oncogenic process involving overexpression of Gs alpha, resulting in chronic activation of adenylate cyclase. Furthermore, our results suggest that the anti-secretory and anti-proliferative effects of bromocriptine may be mediated through a decrease in Pit-1 secondary to the inhibition of adenylate cyclase activity.
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PMID:Mammosomatotroph adenoma causing gigantism in an 8-year old boy: a possible pathogenetic mechanism. 762 75

The aim was to determine whether proton magnetic resonance spectroscopy (MRS) could grade human colorectal cells of differing malignant potential. A cell model of tumour development and progression comprising 2 non-tumorigenic adenoma lines and 4 carcinoma lines of increasing tumorigenicity was chosen. A gradual reduction in cellular differentiation and an accumulation of genetic alterations from adenoma to carcinoma characterized the selected cell lines. One-dimensional and 2-dimensional MRS showed that reduced differentiation in the cell model correlated with an increase in the levels of lipid, metabolites, the glycosylation intermediate uridine diphospho-N-acetylglucosamine and cell-surface fucosylation. Mutations involving the K-ras, APC and DCC genes are present both in adenoma- and in carcinoma-derived lines in this model, but the first evidence of an abnormality in the p53 gene was concomitant with the cells' ability to grow as a tumour in athymic nude mice. This genetic change coincided with the detection, by MRS, of UDP-hexose (ribose moiety, 2D MRS cross peak between H2 at 4.38 ppm and HI at 5.99 ppm) and the appearance of an additional fucosyl resonance (cross peak between-CH3 at 1.41 and H5 at 4.30 ppm) in the least tumorigenic of the carcinoma cell lines. An increase in complexity of the fucosylation spectral pattern was observed with further cellular de-differentiation and increased tumorigenicity. Collectively these data support the existence of an adenoma-carcinoma sequence.
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PMID:Correlation of cellular differentiation in human colorectal carcinoma and adenoma cell lines with metabolite profiles determined by 1H magnetic resonance spectroscopy. 792 26

Allelic expression was examined by single-strand conformation polymorphism analysis in murine fibrosarcomas from inter-subspecific F1 mice between C57BL/6 and MSM. Ten genes encoding p53, mdm2, E-cadherin, 72 kD metalloproteinase and its inhibitor (Timp2), thymidine kinase and four glucose transporters (Gluts) were examined. These genes were chosen because of their probable association with tumor development and progression. In some of the tumors and cell lines, p53, E-cadherin and Glut3 genes showed remarkable differences in allelic expression, one allele being poorly expressed. The allele-specificity persisted in nine cell lines obtained by repeated transplantations from one tumor. These results suggest that expression of some genes is allele-specific in tumor cells and the pattern of specificity is stable. Such a decrease or a loss of expression in one of the alleles may be functionally equivalent to the loss of heterozygosity of the gene, and therefore this may confer malignant properties on tumor cells. It is also suggested that differential expression of two alleles is a common event in tumor cells.
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PMID:Difference in allelic expression of genes probably associated with tumor progression in murine fibrosarcomas and cell lines. 796 Nov 3

The p53 tumor suppressor is found to be mutated and abundant in a wide variety of tumors. Within tumors showing rapid growth, the Type II isoform of hexokinase is also highly expressed to facilitate high rates of glucose catabolism, which in turn promote their rapid proliferation. We previously reported isolation of the proximal promoter of the Type II hexokinase gene from the highly glycolytic hepatoma AS-30D (Mathupala, S. P., Rempel, A., and Pedersen, P. L. (1995) J. Biol. Chem. 270, 16918-16925). Here, we show that a p53 protein, exhibiting two point mutations in its cDNA, is abundantly expressed in the AS-30D hepatoma. Co-expression studies showed that p53 overexpression significantly and reproducibly activated the Type II hexokinase promoter. Two functional p53 motifs were identified within this promoter by footprint and gel retardation analyses. Presence of functional p53 response elements on the Type II hexokinase promoter and the positive regulatory effect on the promoter by the mutant p53 indicates that in rapidly growing liver tumors, and perhaps in many other tumors as well, this highly abundant p53 protein plays a role in maintaining a high glycolytic rate. This is the first report of a possible link between loss of cell cycle control in rapidly growing cancer cells and their high glycolytic phenotype.
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PMID:Glucose catabolism in cancer cells. The type II hexokinase promoter contains functionally active response elements for the tumor suppressor p53. 927 38

For more than two-thirds of this century we have known that one of the most common and profound phenotypes of cancer cells is their propensity to utilize and catabolize glucose at high rates. This common biochemical signature of many cancers, particularly those that are poorly differentiated and proliferate rapidly, has remained until recently a "metabolic enigma." However, with many advances in the biological sciences having been applied to this problem, cancer cells have begun to reveal their molecular strategies in maintaining an aberrant metabolic behavior. Specifically, studies performed over the past two decades in our laboratory demonstrate that hexokinase, particularly the Type II isoform, plays a critical role in initiating and maintaining the high glucose catabolic rates of rapidly growing tumors. This enzyme converts the incoming glucose to glucose-6-phosphate, the initial phosphorylated intermediate of the glycolytic pathway and an important precursor of many cellular "building blocks." At the genetic level the tumor cell adapts metabolically by first increasing the gene copy number of Type II hexokinase. The enzyme's gene promoter, in turn, shows a wide promiscuity toward the signal transduction cascades active within tumor cells. It is activated by glucose, insulin, low oxygen "hypoxic" conditions, and phorbol esters, all of which enhance the rate of transcription. Also, the tumor cell uses the tumor suppressor p53, which is usually modified by mutations to debilitate cell cycle controls, to further activate hexokinase gene transcription. This results in both enhanced levels of the enzyme, which binds to mitochondrial porins thus gaining preferential access to mitochondrially generated ATP, and in a decreased susceptibility to product inhibition and proteolytic degradation. Significantly, these multiple strategies all work together to enable tumor cells to develop a metabolic strategy compatible with rapid proliferation and prolonged survival.
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PMID:Aberrant glycolytic metabolism of cancer cells: a remarkable coordination of genetic, transcriptional, post-translational, and mutational events that lead to a critical role for type II hexokinase. 938 94

The lactate dehydrogenase A (LDH-A) gene, whose product participates in normal anaerobic glycolysis and is frequently increased in human cancers, has been identified as a c-Myc-responsive gene. It was of interest, therefore, to compare the effect of glucose deprivation in c-Myc-transformed and nontransformed cells. We observed that glucose deprivation or treatment with the glucose antimetabolite 2-deoxyglucose caused nontransformed cells to arrest in the G0/G1 phase of the cell cycle. In contrast, c-Myc-transformed fibroblasts, lymphoblastoid, or lung carcinoma cells underwent extensive apoptosis. Ectopic expression of LDH-A alone in Rat1a fibroblasts was sufficient to induce apoptosis with glucose deprivation but not with serum withdrawal, suggesting that LDH-A mediates the unique apoptotic effect of c-Myc when glycolysis is blocked. The apoptosis caused by glucose deprivation was blocked by Bcl-2 expression but appeared to be independent of wild-type p53 activity. These studies provide insights on the coupling of glucose metabolism and the cell cycle in c-Myc-transformed cells and may in the future be exploited for cancer therapeutics.
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PMID:A unique glucose-dependent apoptotic pathway induced by c-Myc. 946 46

Exposure of cultured renal (LLC-PK1) cells for 7 weeks to non-cytotoxic concentrations of S-(1,2-dichlorovinyl)-L-cysteine had resulted in the induction of morphologically and biochemically dedifferentiated clones, which retained their altered properties after removal of the chemical. In this study we investigated by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis and direct sequencing if S-(1,2-dichlorovinyl)-L-cysteine-induced LLC-PK1 clones display mutations in the p53 gene in comparison with wild-type clones. In addition, the characteristics of S-(1,2-dichlorovinyl)-L-cysteine-induced clones were compared with clones induced by carcinogens/metabolites of carcinogens with different mechanisms of action: (i) The potent alkylating agent and bacterial mutagen chloroethylcysteine, the key metabolite of the carcinogen dichloroethane; (ii) potassium bromate, a nephrocarcinogen inducing reactive oxygen species, which give rise to the formation of 8OHdG and DNA strand-breaks; (iii) cis-platinum, a bifunctional cross-linking agent and strand-break inducer and (iv) styrene oxide, the main intermediate metabolite of styrene, an epoxide whose carcinogenicity is thought to be based on cytotoxicity. Three essential markers of the physiological integrity and renal tubule origin of the wild-type LLC-PK1 cells were disrupted in all chemical-derived clones: (i) the polarisation of the plasma membrane into a luminal and basolateral part; (ii) the sodium-dependent glucose uptake and (iii) the pH-dependent ammonia production. Compared with the wild-type clones, poly(ADP-ribosyl)ation, a posttranslational modification of nuclear proteins, was clearly increased in clones induced by S-(1,2-dichlorovinyl)-L-cysteine, potassium bromate and cis-platinum. These clones displayed also band shifts of p53 exon 7, indicating mutations, which were confirmed by sequencing: a double mutation consisting of a base substitution followed by one base insertion in the case of S-(1,2-dichlorovinyl)-L-cysteine and potassium bromate and a base substitution in the case of cis-platinum. The base insertions both lead to the formation of the stop codon UGA resulting in loss of protein function.
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PMID:S-(1,2-dichlorovinyl)-L-cysteine-induced dedifferentiation and p53 gene mutations in LLC-PK1 cells: a comparative investigation with S-(2-chloroethyl)cysteine, potassium bromate, cis-platinum and styrene oxide. 957 11

The glycolytic pathway inhibitor 2-deoxyglucose (2-DG) is capable of suppressing the transcription of the human pathogenic papillomavirus type 18 (HPV 18) in cervical carcinoma cells and derived non-tumorigenic somatic cell hybrids at the level of transcription initiation. HPV down-regulation is selective, since other reference genes are not affected or even up-regulated under the same experimental conditions. Moreover, 2-DG appears to restore the normal half-life of the tumor suppressor gene product p53, because the protein is strongly up-regulated after HPV 18 E6/E7 suppression. The observed 2-DG-effect is not cytotoxic and is reversible after refeeding with fresh medium. HPV 18 suppression by 2-DG can be completely abrogated by simultaneous treatment with the intracellular Ca2+ antagonist TMB-8, indicating that Ca2+, a known intracellular "second messenger", is involved in this process. Elevated c-myc and p53 expression appears to be responsible for the time-dependent accumulation of apoptotic cells after prolonged 2-DG treatment. The finding that 2-DG acts selectively against the expression of a human pathogenic papillomavirus strongly suggests that an appropriate level of glycolysis is not only a peculiarity of growing tumors, but even may be an essential prerequisite for the maintenance of virus-specific E6/E7 gene expression. Our results may have substantial implications for the potential therapeutic application of 2-DG or other glucose derivatives in the treatment of precancerous and malignant HPV-associated lesions.
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PMID:Selective down-regulation of human papillomavirus transcription by 2-deoxyglucose. 961 Jul 19


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