Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The etiology of small cell lung cancer (SCLC) is strongly tied to cigarette smoking, and now there is considerable information concerning molecular abnormalities involved in the pathogenesis of SCLC. Autocrine growth factors such as neuroendocrine regulatory peptides (eg, bombesin/gastrin-releasing peptide) are prominent in SCLC. Dominant oncogenes of the Myc family are frequently overexpressed in both SCLC and non-small cell lung cancer (NSCLC), while the K-RAS oncogene is never mutated in SCLC but it is in 30% of NSCLCs. The most frequent genetic abnormalities involve tumor suppressor genes (TSGs). The TSG p53 is mutated in more than 90% of SCLCs and more than 50% of NSCLCs; the retinoblastoma TSG is inactivated in over 90% of SCLC but only 15% of NSCLCs, and p16, the other component of the retinoblastoma/p16 pathway, is almost never abnormal in SCLC but is inactivated in more than 50% of NSCLCs. The FHIT TSG is inactivated in 50% to 70% of all lung cancers. Recently, we completed a genome-wide allelotyping study using approximately 400 polymorphic markers distributed at around 10 cM resolution across the human genome comparing SCLCs and NSCLCs, looking for all possible TSG sites by loss of heterozygosity. We found that, on average, 17 loci showed loss of heterozygosity in individual SCLCs and 22 for NSCLC, with an average size of loss of 50 to 60 cM, and an average frequency of microsatellite abnormalities of five per tumor. There were 22 different "hot spots" for loss of heterozygosity, 13 with a preference for SCLC, seven for NSCLC, and two affecting both. This provides clear evidence on a genome-wide scale that SCLC and NSCLC differ significantly in the TSGs that are inactivated during their pathogenesis. Acquired hypermethylation of the promoter region of key genes has become one of the most common mechanisms that tumors use to inactivate the function of tumor suppressor and other genes. We recently completed a study of tumor-acquired promoter hypermethylation for nine genes (p16, DAPK, MGMT, GSTP1, RAR beta, FHIT, ECAD, p14ARF, and TIMP1). We found differences in the frequency of RAR beta methylation (70% for SCLC and 40% for NSCLCs). Finally, we looked at the bronchial epithelium accompanying SCLC and NSCLC for the occurrence of clonal alterations using precise laser capture microdissection with subsequent allelotyping for polymorphic markers. In NSCLC, we frequently find clones of cells with molecular abnormalities in histologically affected epithelium (eg, carcinoma in situ, dysplasia, hyperplasia) and occasionally in normal-appearing epithelium in the cases of current or former smokers. In SCLC these histologic preneoplastic changes were minimal. However, in studies of histologically normal respiratory epithelium, we found a several-fold increased rate of allele loss in SCLC compared with NSCLC patients. Thus, the smoking-damaged histologically normal epithelium associated with SCLC appeared genetically scrambled and has incurred significantly more damage than the epithelium accompanying NSCLCs. We conclude that SCLC and NSCLCs do not differ significantly in the number of genetic alterations that occur. However, SCLCs do differ significantly from NSCLCs in the specific genetic alterations that occur. In addition, smoking-damaged bronchial epithelium accompanying SCLCs appears to have undergone significantly more acquired genetic damage than that accompanying NSCLCs. Future studies need to identify the specific genes involved at these multiple sites and determine if these provide new tools for early molecular detection and monitoring of chemoprevention efforts, and serve as specific targets for developing new therapies. Semin Oncol 28 (suppl 4):3-13.
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PMID:Molecular genetics of small cell lung carcinoma. 1147 91

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

In this case of a dedifferentiated chondrosarcoma, we searched for genetic or epigenetic alterations in both components of the tumor, the low grade chondroblastic component, and the high grade osteosacomatouscomponent. To date, only little is known about aberrant patterns of DNA methylation in chondrosarcomas. Microdissection was used as a valuable method for clearly separating the tissues. We examined CpG island methylation of 8 tumor suppressor genes and candidate tumor suppressor genes, which are involved in different pathways: cell cycle (p21WAF1, p16INK4, p14ARF), apoptosis (DAPK, FHIT), DNA repair (hMLH1), and cell adherence (E-Cadherin). We found p16INK4 and E-cadherin promotor methylation in the low grade chondroid compartment of the dedifferentiated chondrosarcoma. P16INK4, FHIT, and E-cadherin were methylated in the highly malignant osteosarcomatous compartment of the tumor. Earlier investigations of this chondrosarcoma showed p53 mutation and p53-LOH in the anaplastic component. As shown in this case, it was accompanied by Rb-LOH. Early methylation of p16IK4 and E-cadherin in the chondroid compartment could point to the monoclonal origin of demonstrated dedifferentiated chondrosarcoma. Further alterations, as shown in p53, Rb and FHIT, are responsible for the "switch" to a high grade anaplastic sarcoma.
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PMID:Genetic and epigenetic alterations in tumor progression in a dedifferentiated chondrosarcoma. 1292 47

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

Epigenetic alterations of the histone acetylation play an important role in the regulation of gene expression associated with cell cycles and apoptosis that may affect the chemosensitivity of gastric carcinomas. Recently, a histone deacetylase inhibitor, trichostatin A (TSA), was proven to be a chemo-sensitizer on human erythroleukemia cells. With the aim of improving the chemotherapeutic efficacy of gastric carcinoma, the effect of TSA on the chemosensitivity of several anticancer drugs in gastric carcinoma cells was investigated. Human gastric cancer cell lines, OCUM-8 and MKN-74, and 5 anticancer drugs, 5-fluorouracil (5-FU), paclitaxel (PTX), oxaliplatin (OXA), irinotecan (SN38) and gemcitabine (GEM) were used. In both gastric cancer cell lines, a synergistic anti-proliferative effect by the combination of TSA (30 ng/ml) with 5-FU, PTX or SN38 showed a synergistic anti-proliferative effect in OCUM-8 and MKN-74 cells. TSA increases the expression of p21, p53, DAPK-1 and the DAPK-2 gene in both OCUM-8 and MKN-74 cells. In conclusion, TSA is a promising chemotherapeutical agent in combination with anticancer drugs of 5-FU, PTX and SN38 in gastric cancer cell lines. The up-regulation of p53, p21, DAPK-1 and DAPK-2 might be associated with the synergistic effect of TSA.
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PMID:Histone deacetylase inhibitor, trichostatin A, increases the chemosensitivity of anticancer drugs in gastric cancer cell lines. 1686 56

Dissection of signal transduction pathways has been advanced by classic genetic approaches including targeted gene deletion and siRNA-based inhibition of gene product synthesis. Chemical genetics is a biochemical approach to develop small peptide-mimetic ligands to alter, post-translationally, how an enzyme functions. DAPK-1 was used as a model enzyme to develop selective peptide ligands that modulate its specific activity. The tumor modifier p21 has the most highly conserved elements of a DAPK consensus substrate, including a basic core followed by a hydrophobic core. Therefore, the p21 protein was synthesized in overlapping fragments to acquire a panel of peptide ligands for testing in DAPK binding and phosphorylation assays. Three distinct p21 derived peptide fragments were found to bind to DAPK; however, these had no stimulatory effect on its activity toward in vivo substrates, p21 and MLC. The p21 peptide ligands did, however, strikingly stimulate DAPK activity toward p53, a substrate that shows conservation in the hydrophobic part of its DAPK-1 consensus site. DAPK-1 stimulatory peptides attenuate tryptic cleavage of DAPK-1, suggesting that ligand binding can alter DAPK-1 conformation and lock the enzyme onto its substrate. We, therefore, generated an artificial p53, containing arginine residues N-terminal to the phospho-acceptor site, creating a better DAPK-1 peptide consensus and demonstrated that the Km for p531-66[ET-->RR] and ATP is elevated. The full-length p53E17T18-->R17R18 also functioned as a better Ser20 kinase substrate in vivo. These data suggest that DAPK-1 binding ligands can be generated to elevate its specific activity toward weak substrates and provide an approach to develop genetic assays to alter DAPK-1-specific activity in vivo.
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PMID:Chemical genetics approach to identify peptide ligands that selectively stimulate DAPK-1 kinase activity. 1729 16

Genetic and biochemical studies have shown that Ser(20) phosphorylation in the transactivation domain of p53 mediates p300-catalyzed DNA-dependent p53 acetylation and B-cell tumor suppression. However, the protein kinases that mediate this modification are not well defined. A cell-free Ser(20) phosphorylation site assay was used to identify a broad range of calcium calmodulin kinase superfamily members, including CHK2, CHK1, DAPK-1, DAPK-3, DRAK-1, and AMPK, as Ser(20) kinases. Phosphorylation of a p53 transactivation domain fragment at Ser(20) by these enzymes in vitro can be mediated in trans by a docking site peptide derived from the BOX-V domain of p53, which also harbors the ubiquitin signal for MDM2. Evaluation of these calcium calmodulin kinase superfamily members as candidate Ser(20) kinases in vivo has shown that only CHK1 or DAPK-1 can stimulate p53 transactivation and induce Ser(20) phosphorylation of p53. Using CHK1 as a prototypical in vivo Ser(20) kinase, we demonstrate that (i) CHK1 protein depletion using small interfering RNA can attenuate p53 phosphorylation at Ser(20), (ii) an enhanced green fluorescent protein (EGFP)-BOX-V fusion peptide can attenuate Ser(20) phosphorylation of p53 in vivo, (iii) the EGFP-BOX-V fusion peptide can selectively bind to CHK1 in vivo, and (iv) the Deltap53 spliced variant lacking the BOX-V motif is refractory to Ser(20) phosphorylation by CHK1. These data indicate that the BOX-V motif of p53 has evolved the capacity to bind to enzymes that mediate either p53 phosphorylation or ubiquitination, thus controlling the specific activity of p53 as a transcription factor.
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PMID:The MDM2 ubiquitination signal in the DNA-binding domain of p53 forms a docking site for calcium calmodulin kinase superfamily members. 1733 37


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