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)

Colorectal cancer is a significant cause of morbidity and mortality in Western populations. This cancer develops as a result of the pathologic transformation of normal colonic epithelium to an adenomatous polyp and ultimately an invasive cancer. The multistep progression requires years and possibly decades and is accompanied by a number of recently characterized genetic alterations. Mutations in two classes of genes, tumor-suppressor genes and proto-oncogenes, are thought to impart a proliferative advantage to cells and contribute to development of the malignant phenotype. Inactivating mutations of both copies (alleles) of the adenomatous polyposis coli (APC) gene--a tumor-suppressor gene on chromosome 5q--mark one of the earliest events in colorectal carcinogenesis. Germline mutation of the APC gene and subsequent somatic mutation of the second APC allele cause the inherited familial adenomatous polyposis syndrome. This syndrome is characterized by the presence of hundreds to thousands of colonic adenomatous polyps. If these polyps are left untreated, colorectal cancer develops. Mutation leading to dysregulation of the K-ras protooncogene is also thought to be an early event in colon cancer formation. Conversely, loss of heterozygosity on the long arm of chromosome 18 (18q) occurs later in the sequence of development from adenoma to carcinoma, and this mutation may predict poor prognosis. Loss of the 18q region is thought to contribute to inactivation of the DCC tumor-suppressor gene. More recent evidence suggests that other tumor-suppressor genes--DPC4 and MADR2 of the transforming growth factor beta (TGF-beta) pathway--also may be inactivated by allelic loss on chromosome 18q. In addition, mutation of the tumor-suppressor gene p53 on chromosome 17p appears to be a late phenomenon in colorectal carcinogenesis. This mutation may allow the growing tumor with multiple genetic alterations to evade cell cycle arrest and apoptosis. Neoplastic progression is probably accompanied by additional, undiscovered genetic events, which are indicated by allelic loss on chromosomes 1q, 4p, 6p, 8p, 9q, and 22q in 25% to 50% of colorectal cancers. Recently, a third class of genes, DNA repair genes, has been implicated in tumorigenesis of colorectal cancer. Study findings suggest that DNA mismatch repair deficiency, due to germline mutation of the hMSH2, hMLH1, hPMS1, or hPMS2 genes, contributes to development of hereditary nonpolyposis colorectal cancer. The majority of tumors in patients with this disease and 10% to 15% of sporadic colon cancers display microsatellite instability, also know as the replication error positive (RER+) phenotype. This molecular marker of DNA mismatch repair deficiency may predict improved patient survival. Mismatch repair deficiency is thought to lead to mutation and inactivation of the genes for type II TGF-beta receptor and insulin-like growth-factor II receptor. Individuals from families at high risk for colorectal cancer (hereditary nonpolyposis colorectal cancer or familial adenomatous polyposis) should be offered genetic counseling, predictive molecular testing, and when indicated, endoscopic surveillance at appropriate intervals. Recent studies have examined colorectal carcinogenesis in the light of other genetic processes. Telomerase activity is present in almost all cancers, including colorectal cancer, but rarely in benign lesions such as adenomatous polyps or normal tissues. Furthermore, genetic alterations that allow transformed colorectal epithelial cells to escape cell cycle arrest or apoptosis also have been recognized. In addition, hypomethylation or hypermethylation of DNA sequences may alter gene expression without nucleic acid mutation.
 ...
PMID:Molecular biology of colorectal cancer. 943 4

Transforming growth factor-beta (TGF-beta) inhibits cell proliferation in many cell types, and acquisition of TGF-beta resistance has been linked to tumorigenesis. One class of proteins that plays a key role in the TGF-beta signal transduction pathway is the SMAD protein family. MDM2, a key negative regulator of p53, has recently been shown to suppress TGF-beta-induced growth arrest in a p53-independent manner. Here we show that MDM2 and the structurally related protein MDMX can inhibit the transcriptional activity of ectopically expressed SMAD1, SMAD2, SMAD3, and SMAD4. Immunofluorescence staining indicated that ectopically expressed SMAD4 was present in both the cytoplasm and nucleus, and MDM2 and NIDMX were localized mainly to the nucleus and cytoplasm, respectively. When SMAD4 was coexpressed with either MDM2 or MDMX, nuclear accumulation of SMAD4 was strikingly inhibited. We have no evidence that SMAD4 binds directly to MDM2 or MDMX; hence, the inactivation and nuclear exclusion of SMAD4 by MDM2/MDMX may involve other indirect mechanisms.
 ...
PMID:MDM2 and MDMX inhibit the transcriptional activity of ectopically expressed SMAD proteins. 1053 76

Intensive screening for genetic alteration in colorectal cancer led to the identification of two types of colorectal tumours that are distinct by their carcinogenesis processes. The first group, named LOH (for loss of heterozygosity)-positive, is characterized by hyperploidy and allelic losses involving preferentially chromosome 18q and chromosome 17p. More than two-thirds of colorectal cancers belong to this group. The second group, called multiple microsatellite loci (MSI)-positive cancers, is characterized by genetic instability at microsatellite loci. Although colorectal cancer cells are characterized by specific microsatellite alterations, the same four different signalling pathways, WNT/Wingless pathway, K-ras pathway, transforming growth factor (TGF)beta pathway and p53 pathway, could be implicated in tumour progression. The WNT/Wingless pathway could be altered in two different ways according to whether the cancer cells belong to the group of LOH-positive or MSI-positive tumours. LOH-positive tumours activate the WNT/Wingless signalling pathway through an adenomatous polyposis coli (APC) mutation, whereas the MSI-positive tumours activate this pathway through a beta-catenin stabilizing mutation. Beta-catenin and APC mutations were observed as early as the adenomatous stage of colorectal neoplasia. In TGFbeta pathways LOH-positive tumours inactivated SMAD2 (similar to mother against decapentaplegic drosophilia) or SMAD4, whereas in MSI-positive tumours the TGFbeta type II receptor is frequently deleted. Alteration of these genes correlated closely with the progression of the adenoma to cancer. In the p53 pathway LOH-positive tumours showed frequent p53 mutation, whereas MSI-positive tumours demonstrated BAX (BCL-2-associated X protein)-inactivating mutation. These alterations contribute to the adenoma-carcinoma transition.
 ...
PMID:Sequence of molecular genetic events in colorectal tumorigenesis. 1077 17

Molecular biology studies have led to the identification of two different types of colorectal carcinomas. The first group, called LOH (for loss of heterozygosity), represents 80% of colorectal cancers and is characterised by aneuploidy, allelic losses and a location in the distal colon. The second group displays phenotypic microsatellite instability (MSI-positive tumours), has a near-diploid karyotype and a relatively low frequency of allelic losses. It accounts for 15% of all colorectal cancers and for about 30% of right-sided cancers. Four different pathways have been identified as responsible for tumour progression: the WNT/Wingless, the K-ras, the Transforming growth factor (TGF) and the P53 pathways. The involvement of these pathways depends on the tumour type. In LOH-positive tumours, the WNT/Wingless pathway is activated through an APC mutation, whereas MSI+ tumours do so through a catenin stabilising mutation. The TGFb growth inhibitory pathway is altered either by mutations in the signal transduction molecules SMAD2 and SMAD4 in LOH positive tumours or by mutations of TGFbRII in MSI+ tumours. In the p53 pathway, mutations in BAX may contribute to the adenoma-carcinoma transition just as p53 mutations may do in LOH positive tumours. Until now, cancer phenotype determination has had no clinical implications. However, the predictive value of the MSI status was recently stressed as a predictive factor for response to chemotherapy. Immunohistochemistry could represent a complementary strategy to molecular biology in assessing MSI status. This simple test would allow to screen all colorectal carcinomas for MSI status, which would provide valuable management information in addition to the histological assessment for tumour stage and grade.
 ...
PMID:[Genetic pathways in colorectal cancer: interest for the pathologist]. 1241 Jan 50

To investigate the etiological association of allelic loss at chromosomal regions containing tumor suppressor genes (TSGs) in non-small cell lung cancer (NSCLC) in Taiwan, we examined 48 microdissected NSCLC samples for loss of heterozygosity (LOH) at nine loci where TSGs are localized nearby. The associations of LOH at each locus with clinicoparameters and prognosis were also examined. The frequent LOH was observed using markers, D3S1285 near the FHIT gene (58.3%), D17S938 near the p53 gene (56.7%), D9S925 near the p16 gene (54.5%), and D13S153 near the RB gene (47.6%). The occurrence of LOH at each TSG locus was compared with the patients' clinicoparameters. The incidence of LOH at D17S938 (p53 gene) and D3S4545 (VHL gene) was significantly higher in squamous carcinoma tumors than in adenocarcinoma tumors (P = 0.003 and 0.024, respectively). LOH of these two loci also occurred frequently in tumors from smoker patients compared to that from nonsmoker patients (P = 0.013 and 0.025, respectively). LOH at D13S153 (RB gene) was also associated with smoking (P = 0.008). In addition, the prognostic analyses indicated that the patients with LOH at D18S535 (18q21, near the SMAD2/4 gene) had significantly longer post-operative survival time compared to those without LOH (P = 0.03). Our results suggested that LOH at FHIT, p53, and p16 genes may occur frequently in NSCLC patients in Taiwan. In addition, LOH at p53, RB, and VHL may associate with smoking or squamous carcinoma patients and LOH at SMAD2/4 may be correlated with better prognosis.
 ...
PMID:Loss of heterozygosity at loci of candidate tumor suppressor genes in microdissected primary non-small cell lung cancer. 1251 64

Methionine deprivation imposes a metabolic stress, termed methionine stress, that inhibits mitosis and induces cell cycle arrest and apoptosis. The methionine-dependent central nervous system tumor cell lines DAOY (medulloblastoma), SWB61 (anaplastic oligodendroglioma), SWB40 (anaplastic astrocytoma), and SWB39 (glioblastoma multiforme) were compared with methionine-stress resistant SWB77 (glioblastoma multiforme). The cDNA-oligoarray analysis and reverse transcription-PCR verification indicated common changes in gene expression in methionine-dependent cell lines to include up-regulation/induction of cyclin D1, mitotic arrest deficient (MAD)1, p21, growth arrest and DNA-damage-inducible (GADD)45 alpha, GADD45 gamma, GADD34, breast cancer (BRCA)1, 14-3-3sigma, B-cell CLL/lymphoma (BCL)1, transforming growth factor (TGF)-beta, TGF-beta-induced early response (TIEG), SMAD5, SMAD7, SMAD2, insulin-like growth factor binding protein (IGFBP7), IGF-R2, vascular endothelial growth factor (VEGF), TNF-related apoptosis-inducing ligand (TRAIL), TNF-alpha converting enzyme (TACE), TRAIL receptor (TRAIL-R)2, TNFR-related death receptor (DR)6, TRAF interacting protein (I-TRAF), IL-6, MDA7, IL-1B convertase (ICE)-gamma, delta and epsilon, IRF1, IRF5, IRF7, interferon (IFN)-gamma and receptor components, ISG15, p65-NF-kappaB, JUN-B, positive cofactor (PC)4, C/ERB-beta, inositol triphosphate receptor I, and methionine adenosyltransferase II. On the other hand, cyclins A1, A2, B1 and B2, cell division cycle (CDC)2 and its kinase, CDC25 A and B, budding uninhibited by benzimidazoles (BUB)1 and 3, MAD2, CDC28 protein kinase (CKS)1 and 2, neuroepithelial cell transforming gene (NET)1, activator of S-phase kinase (ASK), CDC14B phosphatase, BCL2, TGF-beta activated kinase (TAK)1, TAB1, c-FOS, DNA topoisomerase II, DNA polymerase alpha, dihydrofolate reductase, thymidine kinase, stathmin, and MAP4 were down-regulated. In the methionine stress-resistant SWB77, only 20% of the above genes were affected, and then only to a lesser extent. In addition, some of the changes observed in SWB77 were opposite to those seen in methionine-dependent tumors, including expression of p21, TRAIL-R2, and TIEG. Despite similarities, differences between methionine-dependent tumors were substantial, especially in regard to regulation of cytokine expression. Western blot analysis confirmed that methionine stress caused the following: (a) a marked increase of GADD45alpha and gamma in the wt-p53 cell lines SWB61 and 40; (b) an increase in GADD34 and p21 protein in all of the methionine-dependent lines; and (c) the induction of MDA7 and phospho-p38 in DAOY and SWB39, consistent with marked transcriptional activation of the former under methionine stress. It was additionally shown that methionine stress down-regulated the highly active phosphatidylinositol 3'-kinase pathway by reducing AKT phosphorylation, especially in DAOY and SWB77, and also reduced the levels of retinoblastoma (Rb) and pRb (P-ser780, P-ser795, and P-ser807/811), resulting in a shift in favor of unphosphorylated species in all of the methionine-dependent lines. Immunohistochemical analysis showed marked inhibition of nuclear translocation of nuclear factor kappaB under methionine stress in methionine-dependent lines. In this study we show for the first time that methionine stress mobilizes several defined cell cycle checkpoints and proapoptotic pathways while coordinately inhibiting prosurvival mechanisms in central nervous system tumors. It is clear that methionine stress-induced cytotoxicity is not restricted by the p53 mutational status.
 ...
PMID:Modulation of gene expression in human central nervous system tumors under methionine deprivation-induced stress. 1549 78

Knowledge about the in vivo role of endothelium in chronic human atherosclerosis has mostly been derived by insights from mouse models. Therefore, we set out to establish by microarray analyses the gene expression profiles of endothelium from human large arteries, as isolated by laser microbeam microdissection, having focal atherosclerosis of the early or the advanced stage. Within individual arteries, the endothelial transcriptomes of the lesional and unaffected sides were compared pairwise, thus limiting genetic and environmental confounders. Specific endothelial signature gene sets were identified with changed expression levels in either early (n = 718) or advanced atherosclerosis (n = 403), relative to their paired plaque-free controls. Gene set enrichment analysis identified distinct sets of chemokines and differential enrichments of nuclear factor-kappaB-, p53-, and transforming growth factor-beta-related genes in advanced plaques. Immunohistochemistry validated the discriminative value of corresponding endothelial protein expression between early (fractalkine/CX3CL1, IP10/CCL10, TBX18) or advanced (BAX, NFKB2) stages of atherosclerosis and versus their plaque-free controls. The functional involvement of transforming growth factor-beta signaling in directing its downstream gene repertoire was substantiated by a consistent detection of activated SMAD2 in advanced lesions. Thus, we identified truly common, local molecular denominators of pathological changes to vascular endothelium, with a marked distinction of endothelial phenotype between early and advanced plaques.
 ...
PMID:Distinctive expression of chemokines and transforming growth factor-beta signaling in human arterial endothelium during atherosclerosis. 1759 77

Both transforming growth factor beta (TGF-beta) and p53 have been shown to control normal cell growth. Acquired mutations either in the TGF-beta signaling pathway or in the p53 protein were shown to induce malignant transformation. Recently, cross talk between wild-type p53 and the TGF-beta pathway was observed. The notion that mutant p53 interferes with the wild-type p53-induced pathway and acts by a "gain-of-function" mechanism prompted us to investigate the effect of mutant p53 on the TGF-beta-induced pathway. In this study, we show that cells expressing mutant p53 lost their sensitivity to TGF-beta1, as observed by less cell migration and a reduction in wound healing. We found that mutant p53 attenuates TGF-beta1 signaling. This was exhibited by a reduction in SMAD2/3 phosphorylation and an inhibition of both the formation of SMAD2/SMAD4 complexes and the translocation of SMAD4 to the cell nucleus. Furthermore, we found that mutant p53 attenuates the TGF-beta1-induced transcription activity of SMAD2/3 proteins. In searching for the mechanism that underlies this attenuation, we found that mutant p53 reduces the expression of TGF-beta receptor type II. These data provide important insights into the molecular mechanisms that underlie mutant p53 "gain of function" pertaining to the TGF-beta signaling pathway.
 ...
PMID:Mutant p53 attenuates the SMAD-dependent transforming growth factor beta1 (TGF-beta1) signaling pathway by repressing the expression of TGF-beta receptor type II. 1787 24

Ulcerative colitis (UC)-related intraepithelial neoplasia and its distinction from regenerative changes and sporadic adenomas occurring in UC is one of the greatest challenges in gastrointestinal pathology. Recently, the molecular changes in UC-related neoplastic progression have been determined and compared with the molecular changes in sporadic carcinogenesis. Diagnostically promising differences between sporadic and UC-related carcinogenesis are the advent of genetic changes in non-neoplastic UC-related mucosa and the early loss of 18q (harbouring SMAD2, SMAD4, and DCC) and 17p (site of p53) in UC-related tumorigenesis. These studies have given rise to a number of adjunct methods in the determination of UC-related neoplasia. Never the less, conventional histopathology still remains the gold standard in the diagnosis of UC-related neoplasia. Training of histopathologists therefore is one of the most important issues in conquering the diagnostic challenges of UC-related neoplasia. The working group "Gastrointestinal Pathology" of the German Society for Pathology set up a diagnostic multicenter trial which was open to everyone interested. The interobserver variability regarding ulcerative colitis-related neoplasia was quite promising (kappa = 0.63). A consensus diagnosis was reached for all the specimens and diagnostic criteria for UC-related neoplasia were discussed, reevaluated, and agreed on. Adjunct methods and emerging markers for the diagnosis of ulcerative colitis-related neoplasia (p53, Ki67, AMACR) and its distinction from regenerative changes and sporadic adenomas occurring in UC (ALM) will be presented and discussed.
 ...
PMID:[Intraepithelial neoplasia in ulcerative colitis: on the way to more diagnostic confidence]. 1831 6

SBDS/7q11 gene mutations underlie the congenital Shwachman Diamond syndrome (SDS), characterized by bone marrow failure and high risk of haematological malignancies. In two cases of SDS with bone marrow failure and isolated del(20q) interphase fluorescence in situ hybridization (I-FISH) found no abnormalities in FHIT/3p14.2, IKZF1/7p13, D7S486/7q31, PTEN/10q23.3, WT1/11p13, ATM/11q23, D13S25/13q14, TP53/17p13, NF1/17q11, SMAD2/18q21, RUNX1/21q22. Fluorescence immunophenotype combined with I-FISH found del(20q) in a totipotent haematopoietic stem cell (CD34(+), CD133(+)) and downstream myelocyte (CD33(+), CD14(+), CD13(+)), erythrocyte (Glycophorin A(+)) and lymphocyte lineages (CD19(+), CD20(+), CD3(+), CD7(+)). These findings and clinical follow-ups confirm the benign course of SDS with isolated del(20q).
 ...
PMID:Totipotent stem cells bearing del(20q) maintain multipotential differentiation in Shwachman Diamond syndrome. 1901 24


1 2 3 4 5 Next >>