Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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.
 ...
PMID:Phosphorylation of proteins in Clostridium thermohydrosulfuricum. 241 9

Active, recombinant p68 reverse transcriptase (RT) from human immunodeficiency virus type 2 (HIV-2), with an NH2-terminal extension containing a hexahistidine sequence was isolated from extracts of Escherichia coli by immobilized metal affinity chromatography. Treatment of the purified p68/p68 homodimer of HIV-2 RT with recombinant HIV-2 protease generates stable, active heterodimer (p68/p58) that is resistant to further hydrolysis. Analysis of this p68/p58 HIV-2 RT heterodimer revealed that while one subunit is intact p68, the p58 subunit is COOH-terminally truncated by cleavage, not at Phe440 as is seen in processing of the p66/p66 HIV-1 RT homodimer by HIV-1 protease, but at Met484. The expected COOH-terminal p10 fragment resulting from hydrolysis of p68 at Met484 is not released intact, but undergoes further cleavage at Asn494, Met503, and Tyr532. Processing of p68/p68 HIV-2 RT with the HIV-1 protease led to cleavage of the Phe440-Tyr441 bond, exactly as is seen with p66/p66 HIV-1 RT, to give the analogous p53 subunit. Studies of a peptide substrate modeled after residues 437-444 in HIV-2 RT showed that while the HIV-1 protease was able to cleave the Phe440 bond, this bond was resistant to cleavage by the HIV-2 enzyme. Our findings provide a rationale for the previous observation that the RT heterodimer isolated from HIV-2 lysates is larger than that from HIV-1. We conclude that the p68/p58 HIV-2 RT heterodimer, containing the Met484 truncated p58 subunit, is a biologically relevant form of the enzyme in vivo.
 ...
PMID:The differential processing of homodimers of reverse transcriptases from human immunodeficiency viruses type 1 and 2 is a consequence of the distinct specificities of the viral proteases. 753 31

Cell death has been questioned as a mechanism of ventricular failure. In this report, we tested the hypothesis that apoptotic death of myocytes, endothelial cells, and fibroblasts is implicated in the development of the dilated myopathy induced by ventricular pacing. Accumulation of reactive oxygen products such as nitrotyrosine, potentiation of the oxidative stress response by p66(shc) expression, formation of p53 fragments, release of cytochrome c, and caspase activation were examined to establish whether these events were coupled with apoptotic cell death in the paced dog heart. Myocyte, endothelial cell, and fibroblast apoptosis was detected before indices of severe impairment of cardiac function became apparent. Cell death increased with the duration of pacing, and myocyte death exceeded endothelial cell and fibroblast death throughout. Nitrotyrosine formation and p66(shc) levels progressively increased with pacing and were associated with cell apoptosis. Similarly, p50 (DeltaN) fragments augmented paralleling the degree of cell death in the failing heart. Moreover, cytochrome c release and activation of caspase-9 and -3 increased from 1 to 4 weeks of pacing. In conclusion, cardiac cell death precedes ventricular decompensation and correlates with the time-dependent deterioration of function in this model. Oxidative stress may be critical for activation of apoptosis in the overloaded heart.
 ...
PMID:Oxidative stress-mediated cardiac cell death is a major determinant of ventricular dysfunction and failure in dog dilated cardiomyopathy. 1148 69

High embryo loss occurs in the first week of bovine embryo development, with a high percentage of embryonic arrest. We hypothesized that arrested embryos enter a 'senescence-like state' and that both the cell cycle regulatory protein p53 and the stress-related protein p66(shc), which are involved in the onset of senescence in somatic cells, are responsible for this early embryonic arrest. In our in vitro production system, 13.5 +/- 0.5% of embryos arrest at the 2-4-cell stage. First cleavage occurs between 26 and 48 h post insemination (hpi), with early cleaving embryos showing only 0.6 +/- 0.3% arrest, with later cleaving embryos exhibiting up to 14.2 +/- 0.9% arrest. We compared 2-4-cell embryos collected at 28 hpi with those arrested at the 2-4-cell stage collected at day 8 post insemination. Quantification by real-time PCR and by semi-quantitative immunofluorescence showed significantly higher p66(shc) mRNA and protein levels in both arrested and late cleaving embryos versus 28 hpi embryos. By comparison, no significant changes in p53 mRNA, protein and phosphorylation levels were detected. Taken together, these results demonstrate that embryonic developmental potential is related to the time of first cleavage and that p66(shc), but not p53, is up-regulated in early arrested in vitro-produced bovine embryos.
 ...
PMID:p66shc, but not p53, is involved in early arrest of in vitro-produced bovine embryos. 1506 48

Somatic cells undergo a permanent cell cycle arrest, called cellular senescence, after a limited number of cell divisions in vitro. Both the tumor suppressor protein p53 and the stress-response protein p66(shc) are suggested to regulate the molecular events associated with senescence. This study was undertaken to investigate the effect of different oxygen tensions and oxidative stress on cell longevity and to establish the role of p53 and p66(shc) in cells undergoing senescence. As a model of cellular senescence, primary fetal bovine fibroblasts were cultured in either 20% O(2) or 5% O(2) atmospheres until senescence was reached. Fibroblasts cultured under 20% O(2) tension underwent senescence after 30 population doublings (PD), whereas fibroblasts cultured under 5% O(2) tension did not exhibit signs of senescence. Oxidative stress, as measured by protein carbonyl content, was significantly elevated in senescent cells compared to their younger counterparts and to fibroblasts cultured under 5% O(2) at the same PD. p53 mRNA gradually decreased in 20% O(2) cultured fibroblasts until senescence was reached, whereas p53 protein levels were significantly increased as well as p53 phosphorylation on serine 20, suggesting that p53 might be stabilized by posttranslational modifications during senescence. Senescence was also associated with high levels of p66(shc) mRNA and protein levels, while the levels remained low and stable in dividing fibroblasts under 5% O(2) atmosphere. Taken together, our results show an effect of oxidative stress on the replicative life span of fetal bovine fibroblasts as well as an involvement of p53, serine 20-p53 phosphorylation and p66(shc) in senescence.
 ...
PMID:Expression profiles of p53 and p66shc during oxidative stress-induced senescence in fetal bovine fibroblasts. 1530 71

Circumstantial evidence places the p66 isoform of the adapter protein Shc in a position to mediate the accelerated aging phenotype displayed by mice expressing shortened forms of the tumor suppressor protein p53. We present a model in which p66(shc) may be responsible for integrating signals from the p53 pathway with signals from the insulin-like growth factor-1/Daf pathway in mammals. A full understanding of how interactions between p53 and p66(shc) affect longevity will require the production of animals with mutations in the genes encoding both proteins.
 ...
PMID:Ticking fast or ticking slow, through Shc must you go? 1530 71

p66(shc-/-) mice exhibit prolonged lifespan and increased resistance to oxidative and hypoxic stress. To investigate p66(shc) involvement in human longevity, p66(shc) mRNA and protein were evaluated in fibroblasts from young people, elderly and centenarians, exposed to oxidative or hypoxic stress. Unexpectedly, centenarians showed the highest basal levels of p66(shc). Oxidative stress induced p66(shc) in all samples. At variance, hypoxic stress caused p66(shc) reduction only in cells from centenarians. These changes occurred in absence of any modification of p66(shc) promoter methylation pattern. Intriguingly, in cells from centenarians, p66(shc) induction was affected by p53 codon 72 polymorphism. Thus, cells from centenarians present a peculiar regulation of p66(shc), suggesting that its role in mammalian longevity is more complex than previously thought.
 ...
PMID:p66(shc) is highly expressed in fibroblasts from centenarians. 1599 7

p66(Shc) protein has been proposed to be an indispensable factor for p53-dependent, mitochondria-mediated apoptosis in mice. Here, we show that p66(Shc) plays a pro-apoptotic role also in cell lines of human origin such as SaOs-2 and HeLa, where p53 is either absent or inactivated, thus, suggesting that p66(Shc) pro-apoptotic role is independent from the presence of a functional form of p53. The active form of p66(Shc) is phosphorylated in Serine 36. We confirm the importance of Serine 36 phosphorylation for p66(Shc) pro-apoptotic role, and our results suggest that the kinase involved in this process is activated independently from p53.
 ...
PMID:p66(Shc) gene has a pro-apoptotic role in human cell lines and it is activated by a p53-independent pathway. 1648 29

Aging is due to a complex interaction of genetic, epigenetic, and environmental factors, but a strong genetic component appears to have an impact on survival to extreme ages. In order to identify "longevity genes" in humans, different strategies are now available. In our laboratory, we performed association studies on a variety of "candidate" polymorphisms in Italian centenarians. Many genes/polymorphisms gave negative results, while others showed a positive association with human longevity and a sometimes-positive association with unsuccessful aging (myocardial infarction, Alzheimer's disease, and type 2 diabetes). Results regarding genes involved in inflammation (IL-1 cluster, IL-6, IL-10, TNF-alpha, TGF-beta, TLR-4, PPARgamma), insulin/IGF-1 signaling pathway and lipid metabolism (apolipoproteins, CETP, PON1), and oxidative stress (p53, p66(shc)) will be described. In addition, a strong role of the interaction between nuclear and mitochondrial genomes (mtDNA haplogroups and the C150T mutation) emerged from our findings. Thus, the genetics of human longevity appears to be quite peculiar in a context where antagonistic pleiotropy can play a major role and genes can have a different biological role at different ages.
 ...
PMID:The genetics of human longevity. 1680 95

Protein-protein interactions are crucial to biological functions. Consequently, designing drugs to control protein-protein interactions is receiving increasing attention. Protein structures can associate in different ways. Analysis of the structures of protein-protein complexes using amino acid sequence order-independent multiple structural comparison algorithms, led us to conclude that the amino acids Trp, Met, and Phe are important for protein-protein interactions. Hence, in principle, drug design targeting the Trp/Met/Phe should modulate protein functions effectively. Several clusters of the Trp/Met/Phe residues are involved in the p53 protein-protein interactions. The best example in this regard is the Phe19/Trp23 of p53, which binds to transcriptional factors and to the MDM2 protein. In the HIV related proteins, the Trp/Met/Phe residues have roles in the dimerization of the transcriptase (p51/p66) and in cell-fusion processes, including the gp120-CD4 interaction and the gp41 six-helix bundle formation. Trp/Met/Phe residues are preferred in 'normal' functional protein-protein interactions and they also appear to be exploited in amyloid formation, especially the phenylalanine. Comparison of binding propensity and amyloid formation preference reveals that apart from Lysine, Isoleucine is the least structurally conserved in protein binding sites and has a high propensity in sequences forming amyloids. Thus, this may suggest that nature tends to avoid Ile conservation in protein-protein interaction to avoid amyloid formation. In this regards, Trp/Met/Phe as well as Ile may be targeted to modulate protein-protein interaction.
 ...
PMID:Trp/Met/Phe hot spots in protein-protein interactions: potential targets in drug design. 1750 33


1 2 3 4 Next >>