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)

Colorectal cancers (CRCs) are characterized by multiple genetic (mutations) and epigenetic (CpG island methylation) alterations, but it is not known whether these evolve independently through stochastic processes. We have recently described a novel pathway termed CpG island methylator phenotype (CIMP) in CRC, which is characterized by the simultaneous methylation of multiple CpG islands, including several known genes, such as p16, hMLH1, and THBS1. We have now studied mutations in K-RAS, p53, DPC4, and TGFbetaRII in a panel of colorectal tumors with or without CIMP. We find that CIMP defines two groups of tumors with significantly different genetic lesions: frequent K-RAS mutations were found in CIMP(+) CRCs (28/41, 68%) compared with CIMP(-) cases (14/47, 30%, P = 0.0005). By contrast, p53 mutations were found in 24% (10/41) of CIMP(+) CRCs vs. 60% (30/46) of CIMP(-) cases (P = 0.002). Both of these differences were independent of microsatellite instability. These interactions between CIMP, K-RAS mutations, and p53 mutations were preserved in colorectal adenomas, suggesting that they occur early in carcinogenesis. The distinct combinations of epigenetic and genetic alterations in each group suggest that activation of oncogenes and inactivation of tumor suppressor genes is related to the underlying mechanism of generating molecular diversity in cancer, rather than simply accumulate stochastically during cancer development.
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PMID:Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype. 1063 44

Promoter hypermethylation represents a primary mechanism in the inactivation of tumor suppressor genes during tumorigenesis. To determine the frequency and timing of hypermethylation during carcinogenesis of astrocytic tumors, we analysed promoter methylation status of ten tumor-associated genes (MGMT, GSTP1, DAPK, p14ARF, THBS1, TIMP-3, p73, p16INK4A, RB1 and TP53) in a series of 88 astrocytic gliomas, including 24 diffuse astrocytomas; 21 anaplastic astrocytomas, and 43 glioblastomas (33 primary and 10 secondary), as well as two non-neoplastic brain samples, by methylation-specific PCR. Aberrant CpG island methylation was detected in all ten genes analysed, and all but one sample displayed anomalies in at least one gene. The methylation index (number methylated genes/total genes analysed) was 0.3, 0.38, 0.33 and 0.29 for diffuse astrocytomas, anaplastic astrocytomas and secondary and primary glioblastomas, respectively. Some differences may be established regarding the methylation profiles of specific genes and tumor types: MGMT, THBS1, TIMP-3, and p16INK4A appear hypermethylated in low-grade tumors (at least in 45% of cases), whereas GSTP1, DAPK, and p14ARF are mostly changed in 15-50% of the higher grade forms versus <10% in low-grade tumors. Some variation also exists regarding the methylation values for p73 and RB1 (10-40% of cases) among all groups. TP53 presented hypermethylation rates <10% in all tumor subtypes. Our findings thus suggest that methylation represents a common mechanism that contributes to inactivating cancer-related genes in astrocytic neoplasms. This epigenetic change is, in general, an early event in the development of astrocytic neoplasms but this gene silencing mechanism may also appear as a late event involving some loci.
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PMID:Promoter hypermethylation of multiple genes in astrocytic gliomas. 1257 14

Aberrant methylation of CpG islands located in promoter regions represents one of the major mechanisms for silencing of cancer-related genes in tumour cells. We determined the frequency of aberrant CpG island methylation of several tumour-associated genes: MGMT, GSTP1, DAPK, p14ARF, THBS1, TIMP-3, p73, p16INK4A, RB1 and TP53 in 24 neurogenic tumours consisting of pilocytic astrocytomas (n=13) and medulloblastomas (n=11). The methylation index (number methylated genes/total genes analysed) displayed slight differences (0.18 and 0.25, respectively), and the profile of methylated genes in the two neoplasms was distinct, as predicted. The main differences involved the methylation rate of GSTP1 (0% in pilocytic astrocytomas vs. 18% medulloblastomas) and p14ARF (0% in pilocytic astrocytomas vs. 45% in medulloblastomas) genes. Pilocytic astrocytomas also demonstrated some differences when compared to methylation data from other astrocytic tumours, primarily regarding the MGMT methylation rate. Despite the fact that these differences do not show specific tumour-associated gene methylation patterns, our findings should help us understand the pathogenic mechanisms of both neurogenic neoplasm types.
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PMID:Epigenetic changes in pilocytic astrocytomas and medulloblastomas. 1268 7

Promoter hypermethylation represents a primary mechanism in the inactivation of tumor suppressor genes during tumorigenesis. To determine the frequency and timing of hypermethylation during carcinogenesis of nonastrocytic tumors, we analyzed promoter methylation status of 10 tumor-associated genes in a series of 41 oligodendrogliomas (22 World Health Organization [WHO] grade II; 13 WHO grade III; 6 WHO grade II-III oligoastrocytomas) and 7 WHO grade II-III ependymomas, as well as 2 nonneoplastic brain samples, by a methylation-specific polymerase chain reaction. Aberrant CpG island methylation was detected in 9 of 10 genes analyzed, and all but one sample displayed anomalies in at least one gene. The frequencies of hypermethylation for the 10 genes were as follows, in oligodendrogliomas and ependymomas, respectively: 80% and 28% for MGMT; 70% and 28% for GSTP1; 66% and 57% for DAPK; 44% and 28% for TP14(ARF); 39% and 0% for THBS1; 24% and 28% for TIMP3; 24% and 14% for TP73; 22% and 0% for TP16(INK4A); 3% and 14% for RB1; and 0% in both neoplasms for TP53. No methylation of these genes was detected in normal brain tissue samples. We conclude that a high frequency of aberrant methylation of the 5' CpG island of the MGMT, GSTP1, TP14(ARF), THBS1, TIMP3, and TP73 genes is observed in nonastrocytic neoplasms. This aberration seems to occur early in the carcinogenesis process (it is already present in the low-grade forms), although in some instances (DAPK, THBS1, and TP73) it appears also associated with the genesis of anaplastic forms.
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PMID:Aberrant promoter methylation of multiple genes in oligodendrogliomas and ependymomas. 1285 Mar 76

Aberrant methylation of the promoter CpG island of human genes is an alternative gene inactivation mechanism that contributes to the carcinogenesis of human tumours. We have determined the methylation status of the CpG island of 11 tumour-related genes (RB1, p14ARF, p16INK4a, p73, TIMP-3, MGMT, DAPK, THBS1, caspase 8, TP53 and GSTP1) in 18 neurofibromas (including one plexiform neurofibroma) and three neurofibrosarcomas, as well as two non-neoplastic peripheral nerve sheath samples, using methylation-specific polymerase chain reaction. The series included sporadic and neurofibromatosis type 1-associated tumours. The incidence of aberrant methylation in the tumour samples was 52% for THBS1, 43% for MGMT, 33% for TIMP-3, 19% each for p16INK4a and p73, 14% for RB1, 5% for p14ARF, and 0% for DAPK, caspase 8, TP53 and GSTP1. No methylation of these genes was detected in the two samples of non-neoplastic peripheral nerve sheath. All but three samples in the study displayed aberrant methylation in at least one of the studied genes, and there was no correlation between methylation status and the patients' clinical parameters. These findings suggest that methylation of some tumour-related genes may play a significant role in the tumourigenesis of neurofibromas/neurofibrosarcomas.
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PMID:Aberrant CpG island methylation in neurofibromas and neurofibrosarcomas. 1288 34

Epigenetic alterations of DNA methylation play an important role in the regulation of gene expression associated with chemosensitivity of gastric carcinomas. With the aim of improving the chemotherapeutic efficacy of gastric carcinoma, the effect of DNA methyltransferase inhibitor, 5-aza-CdR, on the chemosensitivity of five anticancer drugs was investigated. Human gastric cancer cell lines, OCUM-2M and MKN-74, and five anticancer drugs, 5-FU, PTX, OXA, SN38, and GEM, were used. In both gastric cancer cell lines, a synergistic antiproliferative effect by a combination of 5-aza-CdR at 5 microM was found in SN38 and GEM. 5-Aza-CdR at 5 microM increased apoptosis induced by SN38 and GEM in both cell lines. 5-Aza-CdR increases the expression of DAPK-2 and DAPK-3, RASSF1, and THBS1 genes in both OCUM-2M and MKN-74 cells, but not that of hMLH1, p16, MGMT, E-cadherin, and p53 genes. These findings suggest that 5-aza-CdR is a promising chemotherapeutical agent for gastric carcinomas, in combination with the anticancer drugs SN38 and GEM, in apoptosis signaling. The upregulation of DAPK-2 and DAPK-3, RASSF1, and THBS1 genes by 5-aza-CdR might be associated with the synergistic effect.
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PMID:Synergic antiproliferative effect of DNA methyltransferase inhibitor in combination with anticancer drugs in gastric carcinoma. 1680 21

The nitric oxide (NO) prodrug JS-K is shown to have anticancer activity. To profile the molecular events associated with the anticancer effects of JS-K, HL-60 leukemia cells were treated with JS-K and subjected to microarray and real-time RT-PCR analysis. JS-K induced concentration- and time-dependent gene expression changes in HL-60 cells corresponding to the cytolethality effects. The apoptotic genes (caspases, Bax, and TNF-alpha) were induced, and differentiation-related genes (CD14, ITGAM, and VIM) were increased. For acute phase protein genes, some were increased (TP53, JUN) while others were suppressed (c-myc, cyclin E). The expression of anti-angiogenesis genes THBS1 and CD36 and genes involved in tumor cell migration such as tissue inhibitors of metalloproteinases, were also increased by JS-K. Confocal analysis confirmed key gene changes at the protein levels. Thus, multiple molecular events are associated with JS-K effects in killing HL-60, which could be molecular targets for this novel anticancer NO prodrug.
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PMID:Gene expression profiling for nitric oxide prodrug JS-K to kill HL-60 myeloid leukemia cells. 1934 8

Radiotherapy remains the backbone of head and neck cancer therapy but response is sometimes impeded by tumor radioresistance. Identifying predictive biomarkers of radiotherapy response is a crucial step towards personalized therapy. The aim of this study was to explore gene expression data in search of biomarkers predictive of the response to radiotherapy in head and neck squamous cell carcinoma (HNSCC). Microarray analysis was performed on five cell lines with various intrinsic radiosensitivity, selected from a panel of 29 HNSCC cell lines. The bioinformatics approach included Gene Ontology (GO) enrichment profiling and Ingenuity Pathway Analysis (IPA). The GO-analysis detected 16 deregulated categories from which development, receptor activity, and extracellular region represented the largest groups. Fourteen hub genes (CEBPA, CEBPB, CTNNB1, FN1, MYC, MYCN, PLAU, SDC4, SERPINE1, SP1, TAF4B, THBS1, TP53 and VLDLR) were identified from the IPA network analysis. The hub genes in the highest ranked network, (FN1, SERPINE1, THBS1 and VLDLR) were further subjected to qPCR analysis in the complete panel of 29 cell lines. Of these genes, high FN1 expression associated to high intrinsic radiosensitivity (p=0.047). In conclusion, gene ontologies and hub genes of importance for intrinsic radiosensitivity were defined. The overall results suggest that FN1 should be explored as a potential novel biomarker for radioresistance.
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PMID:Fibronectin 1 is a potential biomarker for radioresistance in head and neck squamous cell carcinoma. 2094 1

Thrombospondin-1 (TSP-1) is an endogenous inhibitor of angiogenesis encoded by the THBS1 gene, whose promoter is activated by p53. In advanced colorectal cancers (CRC), its expression is sustained or even slightly increased despite frequent loss of p53. Here, we determined that in HCT116 CRC cells, p53 activates the THBS1 primary transcript, but fails to boost THBS1 mRNA or protein levels, implying posttranscriptional regulation by microRNAs (miRNA). In a global miRNA gain-of-function screen done in the Dicer-deficient HCT116 variant, several miRNAs negatively regulated THBS1 mRNA and protein levels, one of them being miR-194. Notably, in agreement with published data, p53 upregulated miR-194 expression in THBS1 retrovirus-transduced HCT116 cells, leading to decreased TSP-1 levels. This negative effect was mediated by a single miR-194 complementary site in the THBS1 3'-untranslated region, and its elimination resulted in TSP-1 reactivation, impaired angiogenesis in Matrigel plugs, and reduced growth of HCT116 xenografts. Conversely, transient overexpression of miR-194 in HCT116/THBS1 cells boosted Matrigel angiogenesis, and its stable overexpression in Ras-induced murine colon carcinomas increased microvascular densities and vessel sizes. Although the overall contribution of miR-194 to neoplastic growth is context dependent, p53-induced activation of this GI tract-specific miRNA during ischemia could promote angiogenesis and facilitate tissue repair.
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PMID:p53-responsive miR-194 inhibits thrombospondin-1 and promotes angiogenesis in colon cancers. 2202 25

The gene expression profile of breast cancer has been described as a great breakthrough on the way to comprehend differences in cancer origin, behavior and therapy. However, gene expression profile in histologically normal epithelium (HNEpi) which could harbor genetic abnormalities predisposing breast tissue to develop malignancy was minor scope for scientists in the past. Thus, we aimed to analyze gene expressions in HNEpi and breast cancer tissue (BCTis) in order to establish its value as potential diagnostic marker for cancer development. We evaluated a panel of disease-specific genes in luminal type (A/B) of breast cancer and tumor surrounding HNEpi by qRT-PCR Array in 32 microdissected samples. There was 20.2 and 2.4% deregulation rate in genes with at least 2-fold or 5-fold over-expression between luminal (A/B) type breast carcinomas and tumor surrounding HNEpi, respectively. The high-grade luminal carcinomas showed higher number of deregulated genes compared to low-grade cases (50.6 vs. 23.8% with at least 2-fold deregulation rate). The main overexpressed genes in HNEpi were KLK5, SCGB1D2, GSN, EGFR and NGFR. The significant differences in gene expression between BCTis and HNEpi samples were revealed for BAG1, C3, CCNA2, CD44, FGF1, FOSL1, ID2, IL6R, NGFB, NGFR, PAPPA, PLAU, SERPINB5, THBS1 and TP53 gene (p < 0.05) and BCL2L2, CTSB, ITGB4, JUN, KIT, KLF5, SCGB1D2, SCGB2A1, SERPINE1 (p < 0.01), and EGFR, GABRP, GSN, MAP2K7 and THBS2 (p < 0.001), and GSN, KLK5 (p < 0.0001). The ontological gene analyses revealed high deregulations in gene group directly associated with breast cancer prognosis and origin.
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PMID:Gene expression abnormalities in histologically normal breast epithelium from patients with luminal type of breast cancer. 2540 8


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