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)

Expression of c-Myc sensitizes cells to a wide range of pro-apoptotic stimuli. We here show that this pro-apoptotic effect is mediated through release of mitochondrial holocytochrome c into the cytosol. First, activation of c-Myc triggers release of cytochrome c from mitochondria. This release is caspase-independent and blocked by the survival factor IGF-1. Second, c-Myc-induced apoptosis is blocked by microinjection of anticytochrome c antibody. In addition, we show that microinjection of holocytochrome c mimics the effect of c-Myc activation, sensitizing cells to DNA damage and to the CD95 pathway. Both p53 and CD95/Fas signaling have been implicated in c-Myc-induced apoptosis but neither was required for c-Myc-induced cytochrome c release. Nonetheless, inhibition of CD95 signaling in fibroblasts did prevent c-Myc-induced apoptosis, apparently by obstructing the ability of cytosolic cytochrome c to activate caspases. We conclude that c-Myc promotes apoptosis by causing the release of cytochrome c, but the ability of cytochrome c to activate apoptosis is critically dependent upon other signals.
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PMID:c-Myc-induced sensitization to apoptosis is mediated through cytochrome c release. 1036 55

Mammary gland involution is characterized by extensive apoptosis of the epithelial cells. At the onset of involution, Stat3 is specifically activated. To address the function of this signaling molecule in mammary epithelial apoptosis, we have generated a conditional knockout of Stat3 using the Cre-lox recombination system. Following weaning, a decrease in apoptosis and a dramatic delay of involution occurred in Stat3 null mammary tissue. Involution is normally associated with a significant increase in IGFBP-5 levels. This was observed in control glands, but not in the absence of Stat3. IGFBP-5 has been suggested to induce apoptosis by sequestering IGF-1 to casein micelles, thereby inhibiting its survival function. Our findings suggest that IGFBP-5 is a direct or indirect target for Stat3 and its upregulation is essential to normal involution. No marked differences were seen in the regulation of Stat5, Bcl-x(L), or Bax in the absence of Stat3. Precocious activation of Stat1 and increases in levels of p53 and p21 occurred and may act as compensatory mechanisms for the eventual initiation of involution observed in Stat3 null mammary glands. This is the first demonstration of the importance of a Stat factor in signaling the initiation of physiological apoptosis in vivo.
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PMID:Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3. 1052 4

p53, perhaps the single most important human tumor suppressor, is commonly mutated in human cancers. Normally genotoxic stress and hypoxia activate p53, which, through DNA-specific transcription activation, transcriptional repression, and protein-protein interactions, triggers cell cycle arrest and apoptosis. One of the genes induced by p53 was identified as that encoding the insulin-like growth factor binding protein (IGFBP)-3. IGFBP-3 was originally defined by the somatomedin hypothesis as the principal carrier of IGF-I in the circulation and the primary regulator of the amount of free IGF-I available to interact with the IGF-1 receptor. However, there is accumulating evidence that IGFBP-3 can also cause apoptosis in an IGF-independent manner. Thus, IGFBP-3 induction by p53 constitutes a new means of cross-talk between the p53 and IGF axes, and suggests that the ultimate function of IGFBP-3 may be to serve a protective role against the potentially carcinogenic effects of growth hormone and IGF-I.
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PMID:P53 and IGFBP-3: apoptosis and cancer protection. 1087 90

Stimulation of the local renin-angiotensin system and apoptosis characterize the diabetic heart. Because IGF-1 reduces angiotensin (Ang) II and apoptosis, we tested whether streptozotocin-induced diabetic cardiomyopathy was attenuated in IGF-1 transgenic mice (TGM). Diabetes progressively depressed ventricular performance in wild-type mice (WTM) but had no hemodynamic effect on TGM. Myocyte apoptosis measured at 7 and 30 days after the onset of diabetes was twofold higher in WTM than in TGM. Myocyte necrosis was apparent only at 30 days and was more severe in WTM. Diabetic nontransgenic mice lost 24% of their ventricular myocytes and showed a 28% myocyte hypertrophy; both phenomena were prevented by IGF-1. In diabetic WTM, p53 was increased in myocytes, and this activation of p53 was characterized by upregulation of Bax, angiotensinogen, Ang type 1 (AT(1)) receptors, and Ang II. IGF-1 overexpression decreased these biochemical responses. In vivo accumulation of the reactive O(2) product nitrotyrosine and the in vitro formation of H(2)O(2)-(.)OH in myocytes were higher in diabetic WTM than TGM. Apoptosis in vitro was detected in myocytes exhibiting high H(2)O(2)-(.)OH fluorescence, and apoptosis in vivo was linked to the presence of nitrotyrosine. H(2)O(2)-(.)OH generation and myocyte apoptosis in vitro were inhibited by the AT(1) blocker losartan and the O(2) scavenger TIRON: In conclusion, IGF-1 interferes with the development of diabetic myopathy by attenuating p53 function and Ang II production and thus AT(1) activation. This latter event might be responsible for the decrease in oxidative stress and myocyte death by IGF-1.
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PMID:IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress. 1137 43

Progress in mechanism-based cancer prevention research may be facilitated by the use of animal models displaying specific genetic susceptibilities for cancer such as mice deficient in the p53 tumor suppressor gene, the most frequently altered gene in human cancer. We observed in p53-knockout (p53-/-) mice that calorie restriction (CR; 60% of the control group's intake of carbohydrate energy) increased the latency of spontaneous tumor development (mostly lymphomas) approximately 75%, decreased serum insulin-like growth factor (IGF)-1 and leptin levels, significantly slowed thymocyte cell cycle traverse and induced apoptosis in immature thymocytes. In heterozygous p53-deficient (p53+/-) mice, CR and 1 d/wk of food deprivation each significantly delayed spontaneous tumor development (a mix of lymphomas, sarcomas and epithelial tumors) and decreased serum IGF-1 and leptin levels even when begun late in life. We have also developed a rapid and relevant p53+/- mouse mammary tumor model by crossing p53-deficient mice with MMTV-Wnt-1 transgenic mice, and found that CR and 1 d/wk food deprivation significantly increased mammary tumor latency (greater than twofold) and reduced the mean serum IGF-1 and leptin levels to <50% of that of control mice (P < 0.0001). In addition, fluasterone, fenretinide and soy each delayed tumor development but had little effect on IGF-1 or leptin levels. We have capitalized on the susceptibility of p53+/- mice to chronic, low dose, aromatic amine-induced bladder carcinogenesis to develop a useful model for evaluating bladder cancer prevention approaches such as cyclooxygenase-2 inhibition. As demonstrated by these examples, mice with specific (and human-like) genetic susceptibilities for cancer provide powerful new tools for testing and characterizing interventions that may inhibit the process of carcinogenesis in humans.
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PMID:Diet and cancer prevention studies in p53-deficient mice. 1169 54

Real-time quantitative polymerase chain reaction (PCR) with on-line fluorescence detection has become an important technique not only for determination of the absolute or relative copy number of nucleic acids but also for mutation detection, which is usually done by measuring melting curves. Optimum assay conditions have been established for a variety of targets and experimental setups, but only limited attention has been directed to data evaluation and validation of the results. In this work, algorithms for the processing of real-time PCR data are evaluated for several target sequences (p53, IGF-1, PAI-1, Factor VIIc) and compared to the results obtained by standard procedures. The algorithms are implemented in software called SoFAR, which allows fully automatic analysis of real-time PCR data obtained with a Roche LightCycler instrument. The software yields results with considerably increased precision and accuracy of quantifications. This is achieved mainly by the correction of amplification-independent signal trends and a robust fit of the exponential phase of the signal curves. The melting curve data are corrected for signal changes not due to the melting process and are smoothed by fitting cubic splines. Therefore, sensitivity, resolution, and accuracy of melting curve analyses are improved.
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PMID:Validation of an algorithm for automatic quantification of nucleic acid copy numbers by real-time polymerase chain reaction. 1275 60

In response to oncogenic insults, normal human cells execute a defense response that culminates in cellular suicide, apoptosis. Normal human diploid fibroblasts expressing the human papillomavirus type 16 (HPV-16) E7 oncoprotein are predisposed to apoptosis when they are deprived of growth factors. Even though a dominant negative p53 mutant abrogates the cell death response, it is not accompanied by p53 phosphorylation, the DNA binding capacity of p53 remains unaltered, and no activation of common p53-dependent transcriptional targets is observed. Expression of two insulin-like growth factor-1 binding proteins, IGFBP-2 and -5, is increased presumably in response to enhanced NF-kappaB activity in HPV-16 E7-expressing serum-starved cells. Phosphorylation of AKT, an important modulator of IGF-1 survival signaling, is lower in serum-starved E7-expressing cells, and exogenously added IGF-1 can partially inhibit the cell death response. This suggests that IGFBP-2 and -5 may limit IGF-1 availability thus decreasing survival signaling. Caspase 3 but not caspase 8 is activated in serum-starved HPV-16 E7-expressing cells. Caspase inhibition affects nuclear DNA fragmentation, but cell death is not inhibited. Although mitochondria play important roles in caspase-dependent as well as -independent forms of cell death, there is no evidence for cytochrome c release and thus for mitochondrial permeabilization in growth factor deprived HPV-16 E7-expressing cells.
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PMID:Molecular pathways executing the "trophic sentinel" response in HPV-16 E7-expressing normal human diploid fibroblasts upon growth factor deprivation. 1496 90

Progress in cancer prevention research is being facilitated by the use of animal models displaying specific genetic susceptibilities for cancer, such as mice deficient in one (+/-) or both (-/-) alleles of the p53 tumor suppressor gene. Our lab, which focuses on nutrition (particularly energy balance/obesity) and molecular carcinogenesis, has shown in p53-/- mice that calorie restriction (CR) increases the latency of spontaneous tumor development (mostly lymphomas) approximately 75%, decreases serum insulin-like growth factor (IGF)-1 and leptin levels, and induces apoptosis in immature (lymphoma-susceptible) thymocytes. In heterozygous p53-deficient (p53+/-) mice, CR and a one day/wk fast each significantly delay spontaneous tumor development (a mix of lymphomas, sarcomas, and epithelial tumors) and decreases serum IGF-1 and leptin levels, even when begun late in life. We are presently comparing and combining CR and exercise (treadmill and running wheel) to further elucidate the relationships between energy balance, p53, and tumorigenesis in these models. Furthermore, we have capitalized on the susceptibility of p53+/- mice to chronic, low-dose aromatic amine-induced bladder carcinogenesis to develop a model for evaluating bladder cancer prevention approaches. Using this model, we have established that IGF-1 mediates many of the anti-cancer effects of CR. We are currently conducting oligonucleotide microarray studies to further characterize diet-gene interactions underlying the anti-cancer effects of CR and to determine which of the CR-responsive genes are IGF-1 dependent.
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PMID:Diet-gene interactions in p53-deficient mice: insulin-like growth factor-1 as a mechanistic target. 1533 46

Diabetes mellitus is one of the most common chronic diseases affecting millions of people worldwide. Cardiovascular complication including myocardial infarction is one of the major causes of death in diabetic patients. Diabetes mellitus induces abnormal pathological findings including cell hypertrophy, neuropathy, interstitial fibrosis, myocytolysis and apoptosis and lipid deposits in the heart. In addition, the cytoplasmic organelles of cardiomyocytes including the plasma membrane, mitochondrion and sarcoplasmic reticulum are also impaired in both type I and type II diabetes. Hyperglycaemia is a major aetiological factor in the development of diabetic cardiomyopathy in patients suffering from diabetes. Hyperglycaemia promotes the production of reactive oxygen (ROS) and nitrogen species (RNS). The release of ROS and RNS induces oxidative stress leading to abnormal gene expression, faulty signal transduction and apoptosis of cardiomyocytes. Hyperglycaemia also induces apoptosis by p53 and the activation of the cytochrome c-activated caspase-3 pathway. Stimulation of connective tissue growth factor and the formation of advanced glycation end products in extracellular matrix proteins induces collagen cross-linking and contribute to the fibrosis observed in the interstitium of the heart of diabetic subjects. In terms of signal transduction, defects in intracellular Ca2+ signalling due to alteration of expression and function of proteins that regulate intracellular Ca2+ also occur in diabetes. All of these abnormalities result in gross dysfunction of the heart. Beta-adrenoreceptor antagonists, ACE inhibitors, endothelin-receptor antagonist (Bonestan), adrenomedullin, hormones (insulin, IGF-1) and antioxidants (magniferin, metallothionein, vitamins C and E) reduce interstitial fibrosis and improve cardiac function in diabetic cardiomyopathy.
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PMID:Molecular and cellular basis of the aetiology and management of diabetic cardiomyopathy: a short review. 1536 3

According to the author's theory of gene silencing, the key process in aging involves reduced expression of a number of genes. Silencing of genes has a complex mechanism, which involves methylation of DNA, histone modification and chromatin remodeling. In addition to deacetylation of the histones and methylation of DNA, recently described RNAi mechanism could initiate formation of silenced chromatin. Hypermethylation of the promoter will silence the gene. Genome-wide hypomethylation will induce genomic instability, amplification of oncogenes and also silencing of the genes through RNAi mechanism. Studies by different groups, conducted in yeast, worms, flies and mice, confirmed substantial changes in gene expression in aging. Among them, the most important was silencing of tumor suppressors and other genes involved in the control of cell cycle, apoptosis, detoxification, and cholesterol metabolism. There was also increased expression of the smaller group of oncogenes and other genes which are associated with typical diseases of old age. Caloric restriction normalizes expression of a substantial percentage of these genes. Animal studies confirmed importance of caloric restriction, which decreases signaling through the IGF-1/AKT pathway and expression of gene p53. These studies, however, cannot be directly applied to human aging. It is proposed that age management therapy should attempt to normalize gene expression in the older population to the level typical for young adults. This would require activation of silenced genes and normalization of overexpressed genes. Caloric restriction and exercise are helpful in decreasing the activity of important oncogenes and activation of silenced tumor suppressors, and may have a positive impact, not only on aging, but also on prevention of cancer. Dietary supplements containing phytochemicals should normalize increased expression of oncogenes. Examples are: genistein and EGCG, which effect signaling through the IGF-1/AKT pathway and resveratrol and limonen, which do so through the RAS pathway. A group of amino acid derivatives and organic acids of animal and human origin should activate silenced tumor suppressor genes (Aminocare A10, Aminocare Extra). Among them 3-phenylacetylamino-2, 6-piperidinedione intercalates specifically with DNA and protects sequences of tumor suppressor genes, which are vulnerable to the effects of carcinogens. Phenylacetate activates p53 and p21 through inhibition of methyltransferase and farnesylation of the RAS protein. Phenylbutyrate activates tumor suppressor genes through inhibition of histone deacetylation. Phenylacetylglutamine decreases genomic instability and expression of oncogenes and promotes apoptosis. The application of DNA microarray techniques to human studies should provide more information about differences in gene expression in different age groups and help design more effective age management regimens.
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PMID:Aging: gene silencing or gene activation? 1553 42


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