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)

In normal cells, cell growth and division is controlled by the interplay between proto-oncogenes and tumor suppressor genes. Cancer cells usually have both activated an oncogene and have lost a functional tumor suppressor gene. High level expression of a tumor suppressor, p53, can block the growth of cancer cells. waf1/cip1 is transactivated by the tumor suppressor p53 and the p21waf1/cip1 protein is itself a suppressor of cell growth. To test the effect of growth suppression genes on the growth of cells transformed by individual oncogenes, we have used replication-competent retroviral vectors to induce high level expression of p53 and p21waf1/cip1. Overexpression of p21waf1/cip1 arrests the growth of chicken embryo fibroblasts (CEF) transformed by v-Src, tf-Ras, c-Mos and c-Myc. These data suggest that p21waf1/cip1 might be a useful tool in gene therapy for human cancer.
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PMID:Overexpression of human p21waf1/cip1 arrests the growth of chicken embryo fibroblasts transformed by individual oncogenes. 854 18

We tested the hypothesis that wild-type p53 activity is required for c-Myc-dependent apoptosis in epithelial cells. Primary baby rat kidney epithelial cell lines were generated by immortalization through the concerted action of c-Myc and a temperature-sensitive (ts) dominant inhibitory mutant allele of p53 (BRK myc/p53ts cells). When shifted to the permissive temperature for wild-type p53 activity, the BRK myc/p53ts cells underwent growth arrest and apoptosis. However, apoptosis also could be induced by serum deprivation at the nonpermissive temperature, when p53 was in the mutant state. Bcl-2 suppressed both modes of cell death. Apoptosis induced by wild-type p53 but not by serum deprivation was accompanied by G1 cell cycle arrest and increased expression of the Bcl-2 antagonist Bax. We concluded that c-Myc could induce apoptosis in epithelial cells by at least two mechanisms that could be distinguished by their p53 requirement. Our results support the possibility that c-Myc-dependent cell death might be exploited for therapeutic ends during carcinoma development, without regard to p53 status of the target cell.
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PMID:c-Myc induces apoptosis in epithelial cells by both p53-dependent and p53-independent mechanisms. 857 Jan 93

In this study, we investigated the responses of the T cell leukaemia cell line, CCRF-CEM, and a vincristine-resistant subline, CEM/VCR R, to the induction of cell death by serum withdrawal. This treatment was used to overcome any contribution of P-glycoprotein-mediated drug resistance to the responses of the CEM/VCR R cells. Following serum withdrawal both cell lines exhibited typical apoptotic responses including morphological changes and nucleosomal cleavage of the DNA. However, using several different assays for cell death the CEM/VCR R cell line was shown to undergo apoptosis at a slower rate than the parental CCRF-CEM cell line. Expression of c-Myc, Bcl-2 and p53 was found to be similar in both cell lines, discounting involvement of these proteins in the observed difference in apoptotic response. Given our previous finding that reorganisation of tubulin is involved in apoptosis, we examined the expression of alpha-, beta- and acetylated alpha-tubulin in the parental and resistant lines. The CEM/VCR R cell line had altered tubulin expression when compared to that of the CCRF/CEM line. Transnuclear microtubule networks were observed in log phase CEM/VCR R cells. In addition, increased expression of the acetylated form of the alpha-tubulin isotype suggested that a more stable microtubule network was present in the CEM/VCR R cells. These findings imply that the drug-resistance phenotype in the CEM/VCR R cells may involve the suppression of apoptosis, and that the development of an altered microtubule network may contribute to this suppression.
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PMID:Resistance to apoptotic cell death in a drug resistant T cell leukaemia cell line. 864 60

Mutation, deactivation and disregulated expression of oncogenes and tumour-suppressor genes may be involved in the pathogenesis of oral squamous cell carcinoma (SCC). Deactivation of the p53 tumour-suppressor gene allows cell proliferation and blocks apoptosis of malignant oral keratinocytes. Mutation in the ras oncogene results in persistent mitogenic signalling. Upregulatioed c-Myc expression, in the presence of growth factors, provides an additional proliferative signal. Loss of retinoblastoma tumour-suppressor gene (Rb) function may contribute to oral keratinocyte hyperproliferation and recent evidence suggests that simultaneous deactivation of both p53 and Rb is required for tumourigenesis. Enhanced Bcl-2 and reduced Fas expression inhibit tumour cell apoptosis and may convey resistance to cytotoxic drugs and T cell-mediated cytotoxicity, respectively. Exogenous mutagens such as tobacco, alcohol and viral oncogenes may cause altered expression of oncogenes and tumour-suppressor genes in some cases of oral SCC. The impact of these mechanisms on future therapies for oral SCC is highlighted.
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PMID:Review article: The role of oncogenes, tumour suppressor genes and growth factors in oral squamous cell carcinoma: a case of apoptosis versus proliferation. 870 24

Recent studies have revealed that c-Myc is involved not only in cellular transformation but also in apoptosis induction. However, the intronless myc family genes such as s-myc, N-myc2, mycL2 lack transforming ability and retain only apoptosis inducing activity. Although much remains to be clear regarding the molecular mechanism of apoptosis induction by myc gene expression, our recent results suggest that the intronless myc genes significantly differ from that of the c-myc gene in their requirement for wild-type p53 activity in apoptosis induction. We introduce here recent reports on Myc-mediated apoptosis and discuss its molecular mechanism.
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PMID:[Apoptosis induced by myc family genes]. 874 80

Alkylations at base nitrogens in DNA are removed by excision repair, the first step of which is catalyzed by the repair enzyme N-methylpurine-DNA glycosylase (MPG). To study regulation of MPG expression, we have cloned the rat MPG promoter. A cosmid clone containing the rat MPG gene was isolated from a library using rat MPG cDNA as a probe. The 5' part of the MPG gene and the nontranscribed 5'-flanking region were isolated and characterized. Transcription start sites of the rat MPG gene were identified by primer extension and S1 nuclease protection analysis of RNA from primary rat hepatocytes. Promoter activity of the 5'-flanking noncoding region was shown by transfection in H4IIE rat hepatoma cells of various genomic MPG fragments cloned in front of the reporter gene chloramphenicol acetyltransferase. The rat MPG promoter does not contain a TATA box, but has a CCAAT sequence element and putative binding sites for the transcription factors Sp1, AP-2, AP-3, Ets-1, PEA3, NF-1, p53, c-Myc, NF-kappa B, and the glucocorticoid receptor. The activity of the rat MPG promoter was found to be inducible by the tumor promoter TPA and UV light, but not to a significant extent by methylating agents and ionizing radiation.
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PMID:Isolation and analysis of inducibility of the rat N-methylpurine-DNA glycosylase promoter. 875 39

Apoptosis of HepG2 cells triggered by various agents is characterized in an attempt to delineate the common apoptosis signaling pathway in human hepatoma cells. Several hallmarks of apoptosis, including DNA laddering, chromatin condensation and fragmentation, and an apoptosis specific cleavage of 28S and 18S ribosomal RNA were observed after treatment with curcumin. Curcumin treatment however did not alter the expression levels of Bcl-2 and Bax proteins. p53 protein accumulated slowly and decreased abruptly after reaching the maximum. Conversely, c-Myc protein decreased initially and subsequently increased preceding the onset of apoptosis. The accumulation of p53 protein is not due to increased levels of p53 mRNA and does not result in growth arrest. Staurosporine, quinacrine, ultraviolet irradiation, hydrogen peroxide, and cyclohexamide are all capable of triggering apoptosis in HepG2 cells. While most of these agents affect the expression levels of p53 and c-Myc similarly, none of them altered the expression levels of the Bcl-2 and Bax proteins. In conclusion, these data suggest that p53 and c-Myc may play a more important role in the apoptosis signaling pathway in HepG2 cells, than the bcl-2 gene family.
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PMID:Differential regulation of p53, c-Myc, Bcl-2 and Bax protein expression during apoptosis induced by widely divergent stimuli in human hepatoblastoma cells. 876 Mar 2

The expression of the protein products and mRNA of c-fos, c-myc, p53, and c-raf was examined in normal renal tissues and biopsy specimens from 73 patients with various glomerular diseases. Immunofluorescent staining showed that there were cell nuclei stained for c-Fos, c-Myc, and p53, and cytoplasm positive for c-Raf, in the glomeruli of patients with proliferative types of glomerulonephritis, including IgA nephritis and lupus nephritis, and in patients with focal glomerular sclerosis. Glomerular expression of c-fos and c-myc mRNA was detected by in situ hybridization. The number of proto-oncogene-positive glomerular cells was significantly higher in lupus nephritis, IgA nephritis, and focal segmental sclerosis, as compared with minimal change nephrotic syndrome and normal specimens. In IgA nephritis, the population of glomerular cells positive for c-Fos and c-Myc and the grade of c-Raf immunoreactivity were significantly correlated with the proportion of proliferating cell nuclear antigen (PCNA)-positive glomerular cells, with histological grading of mesangial hypercellularity and matrix increase, and with the magnitude of proteinuria. These data indicate that proto-oncogene expression is associated with mesangial proliferation and matrix expansion in proliferative types of glomerulonephritis and in focal glomerular sclerosis.
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PMID:Proto-oncogene expression in human glomerular diseases. 877 42

Follicular lymphoma is a low grade malignant lymphoma. However, some follicular lymphomas undergo histological transformation into higher grade malignant lymphomas. We recently encountered a diffuse large cell lymphoma which seemed to have progressed from a follicular lymphoma and which finally transformed into a small non-cleaved lymphoma. Each stage of the histological transformation was accompanied by increasing clinical grades of malignancy. It was suspected that in our patient a follicular lymphoma initially developed due to rearrangement of the BCL2 gene, and then underwent histological transformation into a diffuse large cell lymphoma, which was associated with p53 mutation. Subsequent rearrangement of C-MYC promoted the histological transformation of this diffuse large cell lymphoma into a small non-cleaved lymphoma. Our findings indicate that p53 mutation and rearrangement of C-MYC are involved in the histological transformation of follicular lymphomas into more advanced lymphomas.
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PMID:Histological progression of follicular lymphoma associated with p53 mutation and rearrangement of the C-MYC gene. 881 Jan 34

We have developed an animal tumor model system to study the effects of c-Myc activation on apoptosis induction in vivo. Tumors were generated in SCID mice from Rat-1 fibroblasts that constitutively express an inactive c-Myc-estrogen receptor fusion protein (T.D. Littlewood et al, Nucleic Acids Res., 23: 1686 -1690, 1995), which is activated in vivo by the administration of 4-hydroxytamoxifen in time release pellets. We demonstrate that activation of c-Myc results in a substantial increase in the number of apoptotic tumor cells and that this apoptosis is predominant in regions of tumor hypoxia. c-Myc-induced apoptosis of hypoxic cells is inhibited in tumors that overexpress the human Bcl-2 protein. Bcl-2, however, does not prevent p53 protein accumulation or the down-regulation of the cyclin-cdk inhibitor p27 protein following c-Myc activation by 4-hydroxytamoxifen. This result suggests that Bcl-2 does not affect c-Myc function directly but acts downstream of c-Myc to inhibit apoptosis. We propose that the ability of activated c-Myc to enhance cellular proliferation might contribute to the genesis of early neoplasms that are held in check by the alternate ability of c-Myc to induce apoptosis of cells that have outgrown their supply of oxygen or other factors associated with hypoxic regions of solid tumors. Secondary genetic lesions downstream of c-Myc that suppress the apoptotic potential of tumor cells, such as Bcl-2 overexpression, might play an important role in the malignant progression of these tumors because they would disrupt the balance between apoptosis and proliferation initiated by c-Myc deregulation.
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PMID:Modulation of c-Myc activity and apoptosis in vivo. 881 14


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