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)

Prompt reconstitution of hematopoiesis after cytoreductive therapy is essential for patient recovery and may have a positive impact on long-term prognosis. We examined the role of the p53 tumor suppressor gene in hematopoietic recovery in vivo after treatment with the cytotoxic drug 5-fluorouracil (5-FU). We used p53 knock-out (p53-/-) and wild-type (p53+/+) mice injected with 5-FU as the experimental model. Analysis of the repopulation ability and clonogenic activity of hematopoietic stem cells (HSCs) and their lineage-committed descendants showed a greater number of HSCs responsible for reconstitution of lethally irradiated recipients in p53-/- bone marrow cells (BMCs) recovering after 5-FU treatment than in the corresponding p53+/+ BMCs. In post-5-FU recovering BMCs, the percentage of HSC-enriched Lin- Sca-1(+) c-Kit+ cells was about threefold higher in p53-/- than in p53+/+ cells. Although the percentage of the most primitive HSCs (Lin- Sca-1(+) c-Kit+ CD34(low/-)) did not depend on p53, the percentage of multipotential HSCs and committed progenitors (Lin- Sca-1(+) c-Kit+ CD34(high/+)) was almost fourfold higher in post-5-FU recovering p53-/- BMCs than in their p53+/+ counterparts. The pool of HSCs from 5-FU-treated p53-/- BMCs was exhausted more slowly than that from the p53+/+ population as shown in vivo using pre-spleen colony-forming unit (CFU-S) assay and in vitro using long-term culture-initiating cells (LTC-ICs) and methylcellulose replating assays. Clonogenic activity of various lineage-specific descendants was significantly higher in post-5-FU regenerating p53-/- BMCs than in p53+/+ BMCs, probably because of their increased sensitivity to growth factors. Despite all these changes and the dramatic difference in sensitivity of p53-/- and p53+/+ BMCs to 5-FU-induced apoptosis, lineage commitment and differentiation of hematopoietic progenitors appeared to be independent of p53 status. These studies suggest that suppression of p53 function facilitates hematopoietic reconstitution after cytoreductive therapy by: (1) delaying the exhaustion of the most primitive HSC pool, (2) stimulating the production of multipotential HSCs, (3) increasing the sensitivity of hematopoietic cells to growth factors, and (4) decreasing the sensitivity to apoptosis.
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PMID:Role of p53 in hematopoietic recovery after cytotoxic treatment. 953 12

Replicative senescence of human diploid fibroblasts (HDFs) or melanocytes is caused by the exhaustion of their proliferative potential. Stress-induced premature senescence (SIPS) occurs after many different sublethal stresses including H(2)O(2), hyperoxia, or tert-butylhydroperoxide. Cells in replicative senescence share common features with cells in SIPS: morphology, senescence-associated beta-galactosidase activity, cell cycle regulation, gene expression and telomere shortening. Telomere shortening is attributed to the accumulation of DNA single-strand breaks induced by oxidative damage. SIPS could be a mechanism of accumulation of senescent-like cells in vivo. Melanocytes exposed to sublethal doses of UVB undergo SIPS. Melanocytes from dark- and light- skinned populations display differences in their cell cycle regulation. Delayed SIPS occurs in melanocytes from light-skinned populations since a reduced association of p16(Ink-4a) with CDK4 and reduced phosphorylation of the retinoblastoma protein are observed. The role of reactive oxygen species in melanocyte SIPS is unclear. Both replicative senescence and SIPS are dependent on two major pathways. One is triggered by DNA damage, telomere damage and/or shortening and involves the activation of the p53 and p21(waf-1) proteins. The second pathway results in the accumulation of p16(Ink-4a) with the MAP kinase signalling pathway as possible intermediate. These data corroborate the thermodynamical theory of ageing, according to which the exposure of cells to sublethal stresses of various natures can trigger SIPS, with possible modulations of this process by bioenergetics.
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PMID:Cellular and molecular mechanisms of stress-induced premature senescence (SIPS) of human diploid fibroblasts and melanocytes. 1112 81

Following a proliferative phase of variable duration, most normal somatic cells enter a growth arrest state known as replicative senescence. In addition to telomere shortening, a variety of environmental insults and signaling imbalances can elicit phenotypes closely resembling senescence. We used p53(-/-) and p21(-/-) human fibroblast cell strains constructed by gene targeting to investigate the involvement of the Arf-Mdm2-p53-p21 pathway in natural as well as premature senescence states. We propose that in cell types that upregulate p21 during replicative exhaustion, such as normal human fibroblasts, p53, p21, and Rb act sequentially and constitute the major pathway for establishing growth arrest and that the telomere-initiated signal enters this pathway at the level of p53. Our results also revealed a number of significant differences between human and rodent fibroblasts in the regulation of senescence pathways.
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PMID:Role of p14(ARF) in replicative and induced senescence of human fibroblasts. 1156 60

Development is a very robust but far from perfect process, subjected to random variation due to the combined factors that constitute the so-called developmental noise. The effects of early developmental noise may have long-term consequences resulting from slight differences in the make-up and organisation of the former developing system. Here we present evidence suggesting that cancer is not an acquired but an intrinsic process resulting from random factors acting during early development, thus leading to a mixture of susceptibility types that may develop cancer sooner or later, depending on the combination of the environment acting upon such different susceptibility types. We discuss evidence suggesting that some supposedly tumour-suppressor functions, such as those associated with the p53 protein, actually evolved as buffering functions against the early effects of developmental noise that might compromise the stability of embryonic cells and hence of development. Ageing is a stochastic process characterised by progressive failure of somatic maintenance and repair. We put forth the notion that progressive loss of the morphological coherence of the organism (morphological disorder) is a form of ageing, and that morphological disorder is the common theme of most types of cancer. Thus, we suggest that the exhaustion of both developmental constraints and buffering developmental mechanisms link ageing and cancer. Moreover, we propose that cancer may represent one of the most radical forms of ageing, because it generally satisfies the criteria of senescence: intrinsicality, progressiveness and deleteriousness.
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PMID:Developmental noise, ageing and cancer. 1278 15

The p53 tumor suppressor gene was found to play a role in the differentiation of several tissue types. We report here that p53-dependent apoptosis plays a role in the final stages of physiological differentiation of normoblasts, resulting in nuclear condensation and expulsion without cell death. Blood samples of healthy newborns, cord blood as well as bone marrow, were analysed for apoptosis by TUNEL and p53 expression by immunostaining. While some samples exhibited simultaneously several distinct patterns of apoptosis, such as perinuclear, diffused nuclear or nuclear apoptotic bodies, others presented a single defined pattern. Overexpression of p53 protein was detected in normoblasts exhibiting either perinuclear or diffused nuclear p53, corresponding to the nuclear apoptotic pattern in the same sample. Similar results were also evident with colonies cultivated for 12-14 days in culture. Differentiated erythroid colonies exhibited overexpression of p53 and positive TUNEL staining only in the normoblasts. We further examined the state of caspase 3/7 and observed a decrease of this activated enzyme during erythroid differentiation in culture. This study suggests a novel role for apoptosis in normoblast differentiation where nuclear degradation occurs with a delay in the actual cell death. A pivotal role for the p53-dependent apoptosis in the erythroid lineage development is implied. However, this apoptotic process is not fully executed because of the exhaustion in caspase 3/7 and thus cells are diverted towards final stages of differentiation.
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PMID:The onset of p53-dependent apoptosis plays a role in terminal differentiation of human normoblasts. 1287 9

Senescent cells are characterized by the activation of the tumor suppressor protein p53 and consequently their inability to proliferate. However, their phenotype is not restricted to the exhaustion of their replicative potential, as they also exhibit a proinflammatory phenotype, which could possibly contribute to the aging process. Intercellular adhesion molecule-1 (ICAM-1) is one of the molecules involved in inflammatory response that is overexpressed in senescent cells and aged tissues. Although the role of the nuclear factor-kappa B (NF-kappa B) signaling cascade is crucial in ICAM-1 activation, we have shown that p53 directly activates the expression of ICAM-1 in an NF-kappa B-independent manner. This may link p53 to ICAM-1 function and consequently to the aging process and to various age-related pathologies.
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PMID:The proinflammatory phenotype of senescent cells: the p53-mediated ICAM-1 expression. 1524 38

In recent years, an impact of the p53 tumor suppressor protein in the processes of cellular and organismal ageing became evident. First hints were found in model organisms like Saccharomyces cerevisiae, Caenorhabditis elegans, and Drosophila melanogaster where a clear connection between ageing phenotypes and pathways that are regulated by p53, were found. Interestingly, pathways that are central to the ageing process are usually also involved in energy metabolism and are highly conserved throughout evolution. This also supports the long known empiric finding that caloric restriction has a positive impact on the life span of a wide variety of organisms. Within the last years, on the molecular level, an involvement of the insulin-like growth factor and of the histone deacetylase SRIT1 could be shown. Insight on the impact of p53 on ageing at the organismal level came from mice expressing aberrant forms of the p53 protein. Obviously, the balance of the full length p53 protein and of the shorter p44/DeltaNp53 isomer bear a strong impact on ageing. The shorter isoform regulates full length p53 and in cases where there is too much of the longer isoform, this leads to elevated apoptosis resulting in decreased tumor incidence but also in premature ageing due to exhaustion of the renewal potential. Therefore, modulating the expression of the truncated p53 isoform accordingly, might lead to increased health-span and elevated life-span.
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PMID:Cellular and organismal ageing: Role of the p53 tumor suppressor protein in the induction of transient and terminal senescence. 1747 1

SIV-infected macaques exhibit distinct rates of progression to AIDS and despite significant increases in CD8+ T cells, immune cells fail to control and eradicate SIV in vivo. Here, we investigated the interplay between viral reservoir sites, CD8+ T-cell activation/death and outcome. Our data provide strong evidence that mesenteric (Mes) lymph nodes represent major reservoirs not only for SIV-infected macaques progressing more rapidly toward AIDS but also in controllers. We demonstrate that macaques progressing faster display greater expression of TGF-beta and Indoleamine 2,3 dioxygenase in particular in intestinal tissues associated with a phosphorylation of the p53 protein on serine 15 in CD8+ T cells from Mes lymph nodes. These factors may act as a negative regulator of CD8+ T-cell function by inducing a Bax/Bak/Puma-dependent death pathway of effector/memory CD8+ T cells. Greater T-cell death and viral dissemination was associated with a low level of TIA-1+ expressing cells. Finally, we provide evidence that abrogation of TGF-beta in vitro enhances T-cell proliferation and reduces CD8+ T-cell death. Our data identify a mechanism of T-cell exhaustion in intestinal lymphoid organs and define a potentially effective immunological strategy for the modulation of progression to AIDS.
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PMID:TGF-beta in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus. 1761 89

The tumor suppressor p53 is important for inhibiting the development of breast carcinomas. However, little is known about the effects of increased p53 activity on mammary gland development. Therefore, the effect of p53 dosage on mammary gland development was examined by utilizing the p53+/m mouse, a p53 mutant which exhibits increased wild-type p53 activity, increased tumor resistance, a shortened longevity, and a variety of accelerated aging phenotypes. Here we report that p53+/m virgin mice exhibit a defect in mammary gland ductal morphogenesis. Transplants of mammary epithelium into p53+/m recipient mice demonstrate decreased outgrowth of wild-type and p53+/m donor epithelium, suggesting systemic or stromal alterations in the p53+/m mouse. Supporting these data, p53+/m mice display decreased levels of serum IGF-1 and reduced IGF-1 signaling in virgin glands. The induction of pregnancy or treatment of p53+/m mice with estrogen, progesterone, estrogen and progesterone in combination, or IGF-1 stimulates ductal outgrowth, rescuing the p53+/m mammary phenotype. Serial mammary epithelium transplants demonstrate that p53+/m epithelium exhibits decreased transplant capabilities, suggesting early stem cell exhaustion. These data indicate that appropriate levels of p53 activity are important in regulating mammary gland ductal morphogenesis, in part through regulation of the IGF-1 pathway.
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PMID:Altered mammary gland development in the p53+/m mouse, a model of accelerated aging. 1799 64

In higher organisms dependent on the regenerative ability of tissue stem cells to maintain tissue integrity throughout adulthood, the failure of stem cells to replace worn out, dead, or damaged cells is seen as one mechanism that limits life span. In these organisms, tumor suppressors such as p53 are central participants in the control of longevity because they regulate stem cell proliferation. Several recent reports have identified p53 as a longevity gene in organisms such as Caenorhabditis elegans and Drosophila melanogaster, which lack proliferative stem cells in all but the germline and have relatively short life spans. This has forced us to reevaluate the role of p53 in the control of life span. We discuss how p53 might regulate longevity in both long- and short-lived species by controlling the activity of insulin-like molecules that operate in proliferating and non-proliferating compartments of adult somatic tissues. We also discuss the hierarchical structure of life span regulation where loss of p53 has life span extending effects. Finally, we suggest a molecular mechanism by which p53 might facilitate the response to severe nutrient deprivation that allows metabolically active cells to survive periods of starvation. Paradoxically, loss of p53 function in these cells would compromise life span.
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PMID:Running on empty: how p53 controls INS/IGF signaling and affects life span. 1859 47


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