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)

Sunburn cell (SBC) formation in the epidermis is a characteristic consequence of ultraviolet radiation (UVR) exposure at doses around or above the minimum erythema dose. SBC have been identified morphologically and biologically as keratinocytes undergoing apoptosis. There is evidence that SBC formation is a protective mechanism to eliminate cells at risk of malignant transformation. The level of DNA photodamage is a major determinant of SBC induction by a process controlled by the tumor suppressor gene p53. However, extra-nuclear events also contribute to SBC formation, such as the activation of death receptors including CD95/Fas. UVR triggers death receptors either by direct activation of these surface molecules or by inducing the release of their ligands such as CD95 ligand or tumor necrosis factor. Oxidative stress also appears to be involved, probably via mitochondrial pathways, resulting in the release of cytochrome C. Pathways which modify SBC formation are now extensively studied given the importance of apoptosis in eliminating irreparably damaged cells. A greater understanding of the mechanisms that induce and prevent UVR-induced apoptosis will contribute to our understanding of mechanisms relevant in genomic integrity.
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PMID:The molecular determinants of sunburn cell formation. 1138 Jun 10

Cell death by apoptosis is exerted by the coordinated action of many different gene products. Mutations in some of them, acting at different levels in the apoptosis process, have been identified as cause or contributing factor for human diseases. Defects in the transmembrane tumor necrosis factor receptor 1 (TNF-R1) lead to the development of familial periodic fever syndromes. Mutations in the homologous receptor Fas (also named CD95; Apo-1) are observed in malignant lymphomas, solid tumors and the autoimmune lymphoproliferative syndrome type I (ALPS I). A mutation in the ligand for Fas (Fas ligand; CD95 ligand, Apo-1 ligand), which induces apoptosis upon binding to Fas, was described in a patient with systemic lupus erythematodes and lymphadenopathy. Perforin, an other cytotoxic protein employed by T- and NK-cells for target cell killing, is mutated in chromosome 10 linked cases of familial hemophagocytic lymphohistiocytosis. Caspase 10, a representative of the caspase family of proteases, which plays a central role in the execution of apoptosis, is defect in autoimmune lymphoproliferative syndrome type II (ALPS II). The intracellular pro-apoptotic molecule bcl-10 is frequently mutated in mucosa-associated lymphoid tissue (MALT) lymphomas and various non-hematologic malignancies. The p53, an executioner of DNA damage triggered apoptosis, and Bax, a pro-apoptotic molecule with the ability to perturb mitochondrial membrane integrity, are frequently mutated in malignant neoplasms. Anti-apoptotic proteins like bcl-2, cellular-inhibitor of apoptosis protein 2 (c-IAP2) and neuronal apoptosis inhibitory protein 1 (NAIP1) are often altered in follicular lymphomas, MALT lymphomas and spinal muscular atrophy (SMA), respectively. This article reviews the current knowledge on mutations of apoptosis genes involved in the pathogenesis of human diseases and summarises the gradual transformation of discoveries in apoptosis research into benefits for the clinical management of diseases.
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PMID:Mutations in apoptosis genes: a pathogenetic factor for human disease. 1139 50

Fas (CD95/APO-1), a transmembrane glycoprotein and receptor for the Fas ligand, plays an important role in apoptosis. The present study examined whether excitotoxic cell death induces Fas expression in the adult rat brain. Although relatively light immunostaining was observed in control brain sections, significantly increased Fas immunoreactivity was seen from 4 h to 5 days after the onset of kainic acid-induced seizures. Increased expression of both Fas mRNA and protein were also evident by reverse transcription polymerase chain reaction and Western blotting, respectively. Fas induction was correlated with neuronal apoptosis as demonstrated by colocalization of Fas and terminal dT-mediated dUTP nick end-labeling (TUNEL). Cells with increased Fas-expression were also immunoreactive for tumor suppressor p53 and neuronal specific nuclear protein (NeuN). These results suggest that Fas receptor may contribute to excitotoxic neuronal death in cooperation with p53, and further implicates the Fas pathway in the pathophysiology of neurodegenerative diseases.
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PMID:Increased expression of Fas (CD95/APO-1) in adult rat brain after kainate-induced seizures. 1143 33

CD95 (Fas/APO-1) is a death receptor on the surface of a wide variety of cell types. In most cells examined, ionizing radiation acts as a response-enhancing agent for CD95-mediated cell death. Although DNA-damaging radiation appears to modulate CD95-mediated signals through multiple mechanisms, the only well-characterized mechanism is activation of the tumor-suppressor protein p53, which transcriptionally regulates the expression of CD95 on various cell types. The ligand for CD95 is expressed by activated lymphocytes and natural-killer cells, which produce factors that sensitize cells resistant to CD95-mediated cell death. Ligation of CD95 on irradiated tumor cells might be achievable using emerging modalities that reactivate the stalled anti-tumor immune response.
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PMID:Ionizing radiation as a response-enhancing agent for CD95-mediated apoptosis. 1147 95

Adenoviral chimeric tumor suppressor 1 (CTS1) gene transfer was evaluated as a novel approach of somatic gene therapy for malignant glioma. CTS1 is an artificial p53-based gene designed to resist various pathways of p53 inactivation. Here, we report that an adenovirus encoding CTS1 (Ad-CTS1) induces growth arrest and loss of viability in all glioma cell lines examined, in the absence of specific cell cycle changes. In contrast, an adenovirus encoding wild-type p53 (Ad-p53) does not consistently induce apoptosis in the same cell lines. Electron microscopic analysis of Ad-CTS1-infected glioma cells reveals complex cytoplasmic pathology and delayed apoptotic changes. Ad-CTS1 induces prominent activation of various p53 target genes, including p21 and MDM-2, but has no relevant effects on BCL-2 family protein expression. Although Ad-CTS1 strongly enhances CD95 expression at the cell surface, endogenous CD95/CD95 ligand interactions do not mediate CTS1-induced cell death. This is because Ad-CTS1 promotes neither caspase activation nor mitochondrial cytochrome c release and because the caspase inhibitors, z-val-Ala-DL-Asp-fluoromethylketone (zVAD)-fmk or z-Ile-Glu-Thr-Asp- fluoromethylketone (z-IETD)-fmk, do not block CTS1-induced cell death. Ad-CTS1 synergizes with radiotherapy and CD95 ligand in killing glioma cells. In summary, Ad-CTS1 induces an unusual type of cell death that appears to be independent of BCL-2 family proteins, cytochrome c release, and caspases. CTS1 gene transfer is a promising strategy of somatic gene therapy for malignant glioma.
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PMID:Chimeric tumor suppressor 1, a p53-derived chimeric tumor suppressor gene, kills p53 mutant and p53 wild-type glioma cells in synergy with irradiation and CD95 ligand. 1147 23

Defective cytochrome c release and the resulting loss of caspase-3 activation was recently shown to be essential for the susceptibility of human melanoma cells to CD95/Fas-induced apoptosis. Cytochrome c release from mitochondria is regulated by the relative amounts of apoptosis-promoting and apoptosis-inhibiting Bcl-2 proteins in the outer membrane of these organelles. The assignment of Bax/Bcl-2 ratios by quantitative Western blotting in 11 melanoma cell populations revealed a relation to the susceptibility to CD95-mediated apoptosis. We could show that a low Bax/Bcl-2 ratio was characteristic for resistant cells and a high Bax/Bcl-2 ratio was characteristic for sensitive cells. Low Bax expression was not a consequence of mutations in the p53 coding sequence. The Bax/Bcl-2 ratio was also in clear correlation with sensitivity to another cell death inducer, N-acetylsphingosine. Furthermore, Bcl-2 overexpression abolished apoptosis triggered by both apoptotic stimuli, confirming the critical role of the Bax/Bcl-2 ratio as a rheostat that determines the susceptibility to apoptosis in melanoma cells by regulating mitochondrial function. Interestingly, some chemotherapeutics lead to the activation of death pathways by CD95L upregulation, ceramide generation, direct activation of upstream caspases, or upregulation of proapoptotic genes. Taken together, these signals enter the apoptotic pathway upstream of mitochondria, resulting in activation of this central checkpoint. We therefore assumed that apoptosis deficiency of malignant melanoma can be circumvented by drugs directly influencing mitochondrial functions. For this purpose we used betulinic acid, a cytotoxic agent selective for melanoma, straightly perturbing mitochondrial functions. In fact, betulinic acid induced mitochondrial cytochrome c release and DNA fragmentation in both CD95-resistant and CD95-sensitive melanoma cell populations, independent of the Bax/Bcl-2 ratio.
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PMID:The Bax/Bcl-2 ratio determines the susceptibility of human melanoma cells to CD95/Fas-mediated apoptosis. 1151 12

When cervical carcinoma cells were monitored for apoptotic signals, HPV18(+) lines were found to be highly sensitive to agonistic CD95 antibodies or recombinant CD95 ligands after co-exposure with CHX (CD95(S)). In contrast, HPV16(+) cervical carcinoma cells and HPV16-immortalized non-malignant human keratinocytes were CD95-resistant (CD95(R)) under equivalent conditions. Somatic cell hybridization between CD95(S) and CD95(R) cervical carcinoma cell lines revealed that CD95 sensitivity was a dominant trait, which could be correlated with abundant c-Myc and low Bcl-X(L) expression. Although CD95(R) cervical carcinoma cells expressed even higher levels of p53 and CD95 receptor at the surface, resistance could be attributed to the inability to form a functional DISC, necessary for successful transmission of the apoptogenic response. These data indicate that resistance to apoptotic stimuli represents an important immunological escape mechanism during virus-induced carcinogenesis.
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PMID:Differential sensitivity of human papillomavirus type 16(+) and type 18(+) cervical carcinoma cells to CD95-mediated apoptosis. 1151 44

Glioblastoma multiforme (WHO grade IV; GBM) is the most common primary brain tumor with a median survival of less than one year despite multimodal treatment regimens. However, a small subgroup of GBM patients has a better clinical outcome, with a small number of patients surviving several years. Apoptosis, a genetically determined program of cell suicide, may be induced as a consequence of critical DNA damage. However, due to defects in the signaling pathways, cancer cells may escape apoptosis, despite carrying irreversible DNA damage. In the present study, we have analyzed tumors of two age-matched, equally treated groups of GBM patients with different postoperative time to tumor progression (TTP), defined as 'short-term' for TTP of less than 6 months (n = 54), and 'long-term' for TTP of more than 12 months (n = 39) for alterations in apoptosis regulatory pathways: Mutations of the TP53 tumor suppressor gene and/or nuclear accumulation of its gene product p53, expression of Waf/p21, CD95 (Apo1/Fas), and Bcl-2. TP53 mutations were found in 12 out of 54 (22%) GBMs of short-term survivors and 8 out of 35 (23%) tumors of long-term survivors; the respective numbers for nuclear p53 protein accumulation were 12/53 (23%) and 10/37 (27%). Waf1/p21 expression was found in 13/53 (25%) tumors of short-term survivors and 9/35 (26%) GBMs of long-term survivors. The respective numbers for Bcl-2 expression were 25/42 (60%) and 22/36 (61%) and for CD95 (Apo1/Fas) expression 20/49 (41%) and 14/36 (39%) GBMs. The percentage of alterations in genes/proteins involved in the apoptotic pathway investigated here was virtually identical in the two groups of clinically different GBM patients. Thus, our data imply that none of these alterations investigated per se has a strong impact on the overall survival of GBM patients.
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PMID:TP53 gene mutations, nuclear p53 accumulation, expression of Waf/p21, Bcl-2, and CD95 (APO-1/Fas) proteins are not prognostic factors in de novo glioblastoma multiforme. 1151 57

Activated hepatic stellate cells (HSC) are thought to play a pivotal role in development of liver fibrosis which takes place in chronic liver diseases. Previous studies have shown that "activated" rat HSC undergo spontaneous apoptosis probably through the CD95/CD95L pathway. TGF-beta as well as TNF-alpha reduced spontaneous apoptosis and CD95L expression. The aim of this study was to investigate the possible mechanisms responsible for the spontaneous apoptosis and for the anti-apoptotic effect of TGF-beta and TNF-alpha on activated HSC. While bcl-2, bax, NFkappaB and p53 gene expression were spontaneously upregulated, bcl-xL and p21WAF1 gene expression decreased and IkappaB remained unchanged during the activation process in vitro. TGF-beta as well as TNF-alpha induced activation of NFKB and upregulated bcl-xL. The latter was inhibited by overexpression of IkappaB. By suppressing spontaneous apoptosis TGF-beta as well as TNF-alpha inhibited p53 gene expression while that of the p21WAF1 gene was increased. We conclude that TGF-beta as well as TNF-alpha may act as surviving factors for activated rat HSC not only through reduction of CD95L gene expression but also by upregulating the anti-apoptotic factors NFKB, bcl-xL and p21WAF1 and by downregulating the proapoptotic factor p53. The interaction with these factors may lead to the generation of new antifibrotic drugs.
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PMID:The bcl, NFkappaB and p53/p21WAF1 systems are involved in spontaneous apoptosis and in the anti-apoptotic effect of TGF-beta or TNF-alpha on activated hepatic stellate cells. 1156 6

The Fas (APO-1/CD95) system regulates a number of physiological and pathological processes of cell death. The ligand for Fas induces apoptosis by interacting with a transmembrane cell surface Fas receptor. The key role of the Fas system has been studied mostly in the immune system, but Fas mutations, one of the possible mechanisms for resistance to apoptosis signaling, may be involved in the pathogenesis of non-lymphoid malignancies as well. To better understand the potential involvement of Fas system in non-small cell lung cancer (NSCLC) we evaluated Fas and Fas-ligand mRNA expression by polymerase chain reaction in 102 tumor samples and in 44 normal surrounding tissues. Although over 60% of the human NSCLC analysed expressed both genes, they seem to be unable to induce apoptosis in vivo by autocrine suicide. In this regard, we investigated in 79 cases, the promoter and the entire coding region of the Fas gene by polymerase chain reaction, single strand conformation polymorphism and DNA sequencing for detecting putative alterations. Sixteen tumors (20.25 %) were found to have Fas alterations, in promoter and/or exon region. In all cases samples carried heterozygous alterations and mostly showed simultaneous mutations of p53 gene. Moreover, the quantitative analysis of Fas mRNA expression showed high levels of Fas messenger associated with p53 wild-type status alone. Taken together, these findings point to an involvement of Fas/Fas-ligand system in the development of NSCLC, suggesting that the loss of its apoptotic function might be linked to p53 alterations which contribute to the self-maintenance of cancer cells.
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PMID:Alterations of Fas (APO-1/CD 95) gene and its relationship with p53 in non small cell lung cancer. 1164 89


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