Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

In 2003, we began a clinical application of concurrent chemoradiation therapy (CCR) in patients with cervical cancer in our hospital. We analyzed 14 cases of advanced cervical cancer in stages IIa through IIIb by FIGO classification. Tumor size of the uterine cervix ranged from 1.5 cm to 8.0 cm in diameter. Patients received radiation therapy (50 Gy of external beam radiotherapy for pelvis and 20 Gy of high-dose rate intracavitary brachytherapy) combined with chemotherapy. Cisplatin was administered intravenously every 3 weeks at a dose of 70 mg/m(2) during the radiation therapy. In two cases, CCR was stopped because of the side effects. One case developed acute renal failure and another suffered intolerable exhaustion. As for the antitumor effects of CCR, the response rate was 75% (CR 58.3%,PR 16.7%). At the end of the CCR, 10 of 12 patients (83.3%) were negative for viable cells by cytology or biopsy of the uterine cervix. The grade 3 adverse effects were leukopenia, diarrhea and anemia. There was no statistical difference in the overall survival between CCR and radiation therapy alone. The CCR response rate in patients with paraaortic lymph node swelling (suspected metastasis) was low, and they had a poor prognosis. Further examinations for the long-term survival benefit of CCR are necessary.
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PMID:[Concurrent chemoradiation therapy for advanced cervical cancer]. 1787 43

The replicative lifespan of normal somatic cells is restricted by the erosion of telomeres, which are protective caps at the ends of linear chromosomes. The loss of telomeres induces antiproliferative signals that eventually lead to cellular senescence. The enzyme complex telomerase can maintain telomeres, but its expression is confined to highly proliferative cells such as stem cells and tumor cells. The immense regenerative capacity of the hematopoietic system is provided by a distinct type of adult stem cell: hematopoietic stem cells (HSCs). Although blood cells have to be produced continuously throughout life, the HSC pool seems not to be spared by aging processes. Indeed, limited expression of telomerase is not sufficient to prevent telomere shortening in these cells, which is thought ultimately to limit their proliferative capacity. In this review, we discuss the relevance of telomere maintenance for the hematopoietic stem cell compartment and consider potential functions of telomerase in this context. We also present possible clinical applications of telomere manipulation in HSCs and new insights affecting the aging of the hematopoietic stem cell pool and replicative exhaustion.
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PMID:Telomeres, senescence, and hematopoietic stem cells. 1796 Apr 23

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

Programmed death-1 (PD-1)-PD-1 ligand (PD-L) signaling system is involved in the functional impairment of T cells such as in chronic viral infection or tumor immune evasion. We examined PD-L expression in lymphoid cell lines and found that they were up-regulated on Hodgkin lymphoma (HL) and several T-cell lymphomas but not on B-cell lymphomas. PD-L expression was also demonstrated in primary Hodgkin/Reed-Sternberg (H/RS) cells. On the other hand, PD-1 was elevated markedly in tumor-infiltrating T cells of HL, and was high in the peripheral T cells of HL patients as well. Blockade of the PD-1 signaling pathway inhibited SHP-2 phosphorylation and restored the IFN-gamma-producing function of HL-infiltrating T cells. According to these results, deficient cellular immunity observed in HL patients can be explained by "T-cell exhaustion," which is led by the activation of PD-1-PD-L signaling pathway. Our finding provides a potentially effective immunologic strategy for the treatment of HL.
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PMID:PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. 1820 52

Recently, an influential sequencing study found that more than 1700 genes had non-silent mutations in either a breast or colorectal cancer, out of just 11 breast and 11 colorectal tumor samples. This is not surprising given the fact that genomic instability is the hallmark of cancer cells. The plethora of genomic alterations found in every carcinoma does not obey the 'law of genotype-phenotype correlation', since the same histological subtype of cancer harbors different gene mutations and chromosomal aberrations in every patient. In an attempt to make sense out of the observed genetic and chromosomal chaos in cancer, I propose a cascade model. According to this model, tissue regeneration depends on the proliferation and serial activation of stem cells. Replicative telomere erosion limits the proliferative life span of adult stem cells and results in the Hayflick limit (M1). However, local tissue exhaustion or old age might promote the activation of M1-deficient tissue stem cells. Extended proliferation of these cells leads to telomere-driven chromosomal instability and aneuploidy (abnormal balance of chromosomes and/or chromosome material). Several of the aforementioned steps have been already described in the literature. However, in contrast to common theories, it is proposed here that the genomic damage blocks the epigenetic differentiation switch. As a result of aneuploidy, differentiation-specific genes cannot be activated by modification of methylation patterns. Consequently, the phenotype of cancer tissue is largely determined by the epigenetic maturation arrest of tissue stem cells, which in addition enables a fraction of cancer cells to proliferate, invade and metastasize, as normal adult stem cells do. The new model combines genetic and epigenetic alterations of cancer cells in one causative cascade and offers an explanation for why identical histologic cancer types harbor a confusing variety of chromosomal and gene aberrations. The Viennese Cascade, as presented here, may end the debate on if and how 'tumor-unspecific' aneuploidy leads to cancer.
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PMID:Defining the steps that lead to cancer: replicative telomere erosion, aneuploidy and an epigenetic maturation arrest of tissue stem cells. 1829 77

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

Phosphate and tensin homologue deleted on chromosome 10 (PTEN) is a tumor suppressor gene inactivated in numerous sporadic cancers, including melanomas. To analyze Pten functions in melanocytes, we used the Cre-loxP system to delete Pten specifically in murine pigment-producing cells and generated DctCrePten(flox/flox) mice. Half of DctCrePten(flox/flox) mice died shortly after birth with enlargements of the cerebral cortex and hippocampus. Melanocytes were increased in the dermis of perinatal DctCrePten(flox/flox) mice. When the mutants were subjected to repeated depilations, melanocyte stem cells in the bulge of the hair follicle resisted exhaustion and the mice were protected against hair graying. Although spontaneous melanomas did not form in DctCrePten(flox/flox) mice, large nevi and melanomas developed after carcinogen exposure. DctCrePten(flox/flox) melanocytes were increased in size and exhibited heightened activation of Akt and extracellular signal-regulated kinases, increased expression of Bcl-2, and decreased expression of p27(Kip1). Our results show that Pten is important for the maintenance of melanocyte stem cells and the suppression of melanomagenesis.
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PMID:Pten deficiency in melanocytes results in resistance to hair graying and susceptibility to carcinogen-induced melanomagenesis. 1863 29

The objective of the study was to verify the effect of N-acetylcysteine (NAC) supplementation on parameters of oxidative damage and inflammatory response after high-intensity eccentric exercise (EE). 29 participants with a mean age of 21.3+/-4 yr, weight of 74.5+/-7.7 kg, and height of 177.2+/-6.9 cm were selected and divided randomly into 3 groups: placebo (21 days; n=8), NAC (21 days; n=9), and NAC plus placebo (14 days; n=8). Four participants withdrew from the study for personal reasons. 14 days after starting supplementation, the participants performed EE: 3 sets until exhaustion (elbow flexion and extension on the Scott bench, 80% 1RM). Blood samples were collected before and on the 2nd, 4th, and 7th day after EE. Muscle soreness (MS), lipoperoxidation, protein carbonylation, tumor-necrosis factor- (TNF-), and interleukin 10 (IL-10) were determined. Results showed a significant increase in MS in all the groups on the 2nd day after EE and a decrease in the following days. A significant increase was observed in malondialdehyde and carbonyl levels on the 4th and 7th days after EE in all groups. TNF- increased significantly on the 2nd day after eccentric exercise and decreased in the following days irrespective of NAC supplementation; concentration of IL-10 increased significantly on the 4th day in all groups. Only the supplemented groups maintained high levels of IL-10 on the 7th day after EE. The results suggest that treatment with NAC represents an important factor in the defense against muscle soreness and has different effects on oxidative damage and pro- and anti-inflammatory cytokines.
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PMID:N-acetylcysteine supplementation and oxidative damage and inflammatory response after eccentric exercise. 1870 87

The adenomatous polyposis coli (Apc) tumor suppressor is involved in the initiation and progression of colorectal cancer via regulation of the Wnt signaling cascade. In addition, Apc plays an important role in multiple cellular functions, including cell migration and adhesion, spindle assembly, and chromosome segregation. However, its role during adult hematopoiesis is unknown. We show that conditional inactivation of Apc in vivo dramatically increases apoptosis and enhances cell cycle entry of hematopoietic stem cells (HSCs)/ hematopoietic progenitor cells (HPCs), leading to their rapid disappearance and bone marrow failure. The defect in HSCs/HPCs caused by Apc ablation is cell autonomous. In addition, we found that loss of Apc leads to exhaustion of the myeloid progenitor pool (common myeloid progenitor, granulocyte-monocyte progenitor, and megakaryocyte-erythroid progenitor), as well as the lymphoid-primed multipotent progenitor pool. Down-regulation of the genes encoding Cdkn1a, Cdkn1b, and Mcl1 occurs after acute Apc excision in candidate HSC populations. Together, our data demonstrate that Apc is essential for HSC and HPC maintenance and survival.
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PMID:A critical role for Apc in hematopoietic stem and progenitor cell survival. 1872 24


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