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)

Tumour cell invasion and metastasis are the processes which kill most cancer patients. Tumour cells with the greatest invasive and metastatic capacity may be those with the highest number of genetic aberrations. The present study has analysed the expression of several tumour-related proteins in both primary tumours and metastatic lesions from 34 breast cancer patients. Protein expression of p53, bcl-2, p21, cyclin D1, E-cadherin, alpha-catenin, beta-catenin, and gamma-catenin was investigated by immunohistochemistry (IHC) using monoclonal antibodies. Metastatic tissue showed a different expression profile from the primary tumour in most patients. The most significant finding was the re-expression of E-cadherin, alpha-catenin, and beta-catenin, and increased down-regulation of gamma-catenin, in metastatic lesions. These results demonstrate that tumour cells, when released from the primary site and after regrowth elsewhere, are capable of re-expression of adhesion molecules. gamma-catenin may play a different role in metastatic lesions than in primary tumours, since it is selectively down-regulated in tumour tissue at the metastatic site.
 ...
PMID:Re-expression of E-cadherin, alpha-catenin and beta-catenin, but not of gamma-catenin, in metastatic tissue from breast cancer patients [seecomments]. 1064 Sep 85

APCL, a central nervous system-specific sequence homologue of the adenomatous polyposis coli tumor suppressor, can regulate the cytoplasmic level of beta-catenin as the adenomatous polyposis coli tumor suppressor does, but its overall biological function remains unclear. Using a yeast two-hybrid system, we attempted to isolate proteins that might associate with the unique COOH-terminus of APCL. Among 166 cDNA clones isolated from a human fetal-brain cDNA library as candidates for interaction with APCL, 32 encoded parts of p53-binding protein 2 (53BP2), a molecule that interacts with p53 and Bcl2. An in vitro binding assay indicated that the Src-homology-3 domain and the ankyrin-repeat domain of 53BP2 were both required for binding to the COOH-terminus of APCL. Confocal microscopy showed that APCL and 53BP2 proteins were localized together in the perinuclei of normal mammalian cells, but this was not the case in cells that expressed truncated APCL and 53BP2 proteins. These findings suggested that binding of the COOH-terminus of APCL to 53BP2 regulates the cytoplasmic location of 53BP2. Because 53BP2 also interacts with p53 and Bcl2 and regulates p53 function, our results suggest that APCL might be involved in the p53/Bcl2-linked pathway of cell-cycle progression and cell death.
 ...
PMID:APCL, a central nervous system-specific homologue of adenomatous polyposis coli tumor suppressor, binds to p53-binding protein 2 and translocates it to the perinucleus. 1064 60

The cerebellar medulloblastoma (WHO Grade IV) is a highly malignant, invasive embryonal tumor with preferential manifestation in children. Several molecular alterations appear to be involved, including isochromosome 17q and the p53, PTCH, and beta-catenin gene mutations. In this study, 46 sporadic medulloblastomas were screened for the presence of mutations in genes of the Wnt signaling pathway (APC and beta-catenin). Single-strand conformational polymorphism (SSCP) analysis followed by direct DNA sequencing revealed 3 miscoding APC mutations in 2 (4.3%) medulloblastomas. One case contained a GCA-->GTA mutation at codon 1296 (Ala-->Val), and another case had double point mutations at codons 1472 (GTA-->ATA, Val-->Ile) and 1495 (AGT-->GGT, Ser-->Gly). Miscoding beta-catenin mutations were detected in 4 tumors (8.7%). Three of these were located at codon 33 (TCT -->TTT, Ser-->Phe) and another at codon 37 (TCT-->GCT, Ser-->Ala). Adenomatous polyposis coli (APC) gene and beta-catenin mutations were mutually exclusive and occurred in a total of 6 of 46 cases (13%). Although germline APC mutations are a well established cause of familial colon and brain tumors (Turcot syndrome), this study provides the first evidence that APC mutations are also operative in a subset of sporadic medulloblastomas.
 ...
PMID:APC mutations in sporadic medulloblastomas. 1066 72

Little is known about the genetic mechanisms behind the genesis of anaplastic thyroid carcinoma. This is among the most virulent of all human malignancies, and it is believed to result most often from transformation of differentiated thyroid carcinomas of the papillary type. So far, TP53 and beta-catenin mutations are the only genetic alterations that have been implicated in its pathogenesis. To identify loci of other potential tumor suppressor genes, we carried out a genome-wide allelotyping study using 39 microsatellite markers representing all nonacrocentric autosomal arms, in a panel of 21 anaplastic thyroid carcinomas. Frequent allelic losses were identified in 1q (40%), 9p (58%), 11p (33%), 11q (33%), 17p (44%), 17q (43%), 19p (36%), and 22q (38%). Deletion mapping of chromosome arms with the most frequent allelic losses (frequencies above 40%) localized the commonly deleted region to 1q31-42, 9p21-22, 17p12-ter, and 17q21.1-22. The mean frequency of loss of heterozygosity on all arms tested was 20%, and the mean fractional allelic loss among the cancers examined was 0.20. These findings defined a sharp distinction between anaplastic thyroid carcinomas and papillary thyroid carcinomas, because the latter do not tend to show losses at the same loci. Frequent allelic losses at multiple loci may implicate chromosomal instability as an important factor in the development of anaplastic thyroid carcinomas. Genes Chromosomes Cancer 27:244-251, 2000.
 ...
PMID:Allelotyping of anaplastic thyroid carcinoma: frequent allelic losses on 1q, 9p, 11, 17, 19p, and 22q. 1067 13

The purpose of this study was to assess the prognostic effect of the expression of E-cadherin, beta-catenin and CD44 adhesion molecules in bladder carcinoma. 22 superficial and 18 invasive bladder tumour samples were studied by immunohistochemistry. The median follow-up was 24 months (range: 1-50 months). Loss of E-cadherin and beta-catenin immunoreactivity was found in 14 (35%) and 17 (43%) tumours, respectively, and was significantly associated with invasiveness, high grade and p53 overexpression. There was no correlation between CD44 variant expression and clinicopathological findings. Loss of E-cadherin expression was an independent predictor of poor survival in a multivariate analysis, when assessed with age, grade, stage and p53 status (hazards ratio adjusted (HRa)=4.45 [95% confidence interval (CI), 1.06-18.63]). This effect was particularly augmented in patients with invasive bladder cancer. When expression of E-cadherin and beta-catenin were evaluated simultaneously, loss of immunoreactivity of both proteins was a strong predictor of poor survival (HRa=13.06 [95% CI, 0.95-178.55]). The same pattern was found when progression-free survival in relation to these variables was assessed. In conclusion, assessment of E-cadherin and beta-catenin immunoreactivity may be a useful prognostic marker in bladder cancer complementary to established prognostic factors.
 ...
PMID:Prognostic value of the expression of E-cadherin and beta-catenin in bladder cancer. 1070 37

Patients with long-standing ulcerative colitis (UC) have an increased risk for developing colorectal cancer (CRC) compared to the general population. For investigation of the mechanisms and prevention of UC and UC-related CRC, establishment of a promising animal model for such disease is important. 1-hydroxyanthraquinone (1-HAQ) present in certain medicinal plants such as Rubia tinctorum L. is a genotoxic and rodent colon carcinogen. Long-term feeding of 1-HAQ induced hyper-cell proliferation in rat colonic crypts with ulcerative changes, crypt abscess, severe inflammation and erosion before the occurrence of tumors, which are similar to those found in human UC. In addition, 1-HAQ has a synergistic effect with methylazoxymethaol (MAM) acetate on colon carcinogenesis. The polymerase chain reaction-single strand conformation polymorphism analysis revealed no mutations in Ki-ras and p53 in colonic neoplasms induced by MAM acetate + 1-HAQ, MAM acetate alone or 1-HAQ alone. Also, no mutations of APC were found in these tumors. These findings are similar to those found in human ulcerative colitis-associated colon cancer in contrast with sporadic colon cancers. A previous study revealed that induced colonic tumors had beta-catenin mutation with high frequency, suggesting tumor development by activation of the beta-catenin-Tcf signaling pathway. Increased expression in TNF-alpha and IL-1alpha was found in these induced colonic neoplasms, and the expression was more remarkable in colonic mucosa of rats exposed to MAM acetate + 1-HAQ, MAM acetate or 1-HAQ when compared with that in untreated rats. Thus, these cytokines may act as growth factors in rat colon carcinogenesis by MAM acetate and 1-HAQ and the synergistic effect of 1-HAQ with MAM acetate might be related to the biological effects of the cytokines expressed in the inflammatory conditions induced by 1-HAQ.
 ...
PMID:Colitis-related rat colon carcinogenesis induced by 1-hydroxy-anthraquinone and methylazoxymethanol acetate (Review). 1076 59

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

The intronless N-myc2 gene was originally identified as the major target of hepatitis virus insertion in woodchuck liver tumors. Here we report that transgenic mice carrying the N-myc2 gene controlled by woodchuck hepatitis virus (WHV) regulatory sequences are highly predisposed to liver cancer. In a WHV/N-myc2 transgenic line, hepatocellular carcinomas or adenomas arose in over 70% of mice, despite barely detectable expression of the methylated transgene in liver cells. Furthermore, a transgenic founder carrying unmethylated transgene sequences succumbed to a large liver tumor by the age of two months, demonstrating the high oncogenicity of the woodchuck N-myc2 retroposon. Stabilizing mutations or deletions of beta-catenin were found in 25% of liver tumors and correlated with reduced tumor latency (P<0.05), confirming the important role of beta-catenin activation in Myc-induced tumorigenesis. The ability of the tumor suppressor gene p53 to cooperate with N-myc2 in liver cell transformation was tested by introducing a p53-null allele into WHV/N-myc2 transgenic mice. The loss of one p53 allele in transgenic animals markedly accelerated the onset of liver cancer (P=0.0001), and most tumors of WHV/N-myc2 p53+/Delta mice harbored either a deletion of the wt p53 allele or a beta-catenin mutation. These findings provide direct evidence that activation of N-myc2 and reduction of p53 levels act synergistically during multistage carcinogenesis in vivo and suggest that different genetic pathways may underlie liver carcinogenesis initiated by a myc transgene. Oncogene (2000).
 ...
PMID:Hepatocellular carcinoma in WHV/N-myc2 transgenic mice: oncogenic mutations of beta-catenin and synergistic effect of p53 null alleles. 1085 Oct 67

The genetic mechanisms of carcinomas of the small intestine are not well understood. We report the results of analysis of genetic alterations in a case of small intestinal carcinoma. A tumor in the terminal ileum was resected in a 59-yr-old woman. Histologically, the tumor was classified as well-differentiated adenocarcinoma. We screened for genetic alterations in adenomatous polyposis coli (APC), beta-catenin, K-ras, and p53 genes, as well as microsatellite instability, which are known to be involved in colorectal tumorigenesis. The tumor exhibited somatic interstitial deletion of 425-bp, which included the entire exon 3 in beta-catenin gene. Immunohistochemical staining confirmed accumulation of aberrant beta-catenin protein in the cytoplasm and nuclei of the malignant tissue. Furthermore, a frameshift mutation in the transforming growth factor beta receptor type II gene with replication error phenotype was detected in the tumor DNA. In contrast, no genetic alterations were found in the APC, K-ras, and p53 genes. Our results suggested that both beta-catenin gene mutation and replication error phenotype might contribute to carcinogenesis of the small intestinal tumor in our case. This is the first report that activation of beta-catenin gene by somatic gene mutation is involved in the development of carcinoma of the small intestine.
 ...
PMID:Molecular and biological analysis of carcinoma of the small intestine: beta-catenin gene mutation by interstitial deletion involving exon 3 and replication error phenotype. 1089

CBP and its homologue p300 play significant roles in cell differentiation, cell cycle, and anti-oncogenesis. We demonstrated that beta-catenin, recently known as a potent oncogene, and CBP/p300 are associated through its CH3 region, which is a primary target of adenoviral oncoprotein E1A and various nuclear proteins, such as p53, cyclin E, and AP-1, and both are colocalized in the nuclear bodies. CBP/p300 potentiated Lef-mediated transactivation of beta-catenin, and E1A, a potent inhibitor of CBP/p300, repressed its transactivation. Furthermore, overexpression of stable beta-catenin mutant competitively suppressed the p53-dependent pathway. These may be a key mechanism of beta-catenin involved in oncogenic events underlying disruption of tumor suppressor function through CBP/p300.
 ...
PMID:Regulation of Lef-mediated transcription and p53-dependent pathway by associating beta-catenin with CBP/p300. 1090 19


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>