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)

Human colorectal tumorigenesis is often initiated by APC (adenomatous polyposis coli) or beta-catenin (CTNNB1) mutations, which result in dysregulation of beta-catenin expression, followed by alterations in E-cadherin and/or p53. We examined 32 canine intestinal tumors for expression and intracellular distribution of beta-catenin, E-cadherin, and p53 using immunohistochemistry. beta-Catenin in normal mucosal epithelial cells was restricted to lateral cell membranes, but 13/13 (100%) colorectal adenomas had intense cytoplasmic and/or nuclear reactivity. Three of six (50%) colorectal carcinomas, 2/13 (15%) small intestinal carcinomas, and dysplastic cells in 1/2 focal hyperplastic lesions in the small intestine had a similar pattern of staining; remaining tumors had normal membranous beta-catenin reactivity. There was a correlation (P = 0.007) between abnormal beta-catenin and E-cadherin staining with 11/13 (85%) colorectal adenomas, 3/6 (50%) colorectal carcinomas, and 3/13 (23%) small intestinal carcinomas showing decreased membranous reactivity compared with normal mucosal epithelium. E-cadherin staining was reduced more often in adenomas than in carcinomas (P = 0.04). There were two patterns of nuclear p53 staining: > 60% of nuclei in 2/26 (8%) carcinomas (one colorectal, one small intestinal) were strongly labeled, whereas three colorectal adenomas and one small intestinal carcinoma had fainter staining in 10-20% of cells. Dysregulation of beta-catenin appears to be as important in canine colorectal tumorigenesis as it is in the human disease and could be due to analogous mutations. Malignant progression in canine intestinal tumors does not appear to be dependent on loss of E-cadherin or beta-catenin expression or strongly associated with overexpression of nuclear CMI antibody-reactivity p53.
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PMID:Dysregulation of beta-catenin is common in canine sporadic colorectal tumors. 1033 31

A 42 year old man without familial adenomatous polyposis had recurrent desmoid tumours in the left subclavicular site. Histological examination showed a typical desmoid tumour. Molecular analysis was performed in genomic DNA from this tumour, using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and direct sequencing methods. No mutation could be detected in the entire coding sequence of the APC gene, nor in H-ras, K-ras, N-ras, or p53 genes. On seeking a mutation of the beta catenin gene (CTNNB1), an activating mutation from ACC (Thr) to GCC (Ala) at codon 41 was found. Immunohistochemical staining showed that accumulated beta catenin protein was predominantly localised in the nuclei of desmoid cells. This is the first example of a sporadic desmoid tumour in which a mutation of the beta catenin gene was revealed.
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PMID:A novel case of a sporadic desmoid tumour with mutation of the beta catenin gene. 1065 94

beta-catenin is involved in both cell-cell interactions and wnt pathway-dependent cell fate determination through its interactions with E-cadherin and TCF/LEF transcription factors, respectively. Cytoplasmic/nuclear levels of beta-catenin are important in regulated transcriptional activation of TCF/LEF target genes. Normally, these levels are kept low by proteosomal degradation of beta-catenin through Axin1- and APC-dependent phosphorylation by CKI and GSK-3beta. Deregulation of beta-catenin degradation results in its aberrant accumulation, often leading to cancer. Accordingly, aberrant accumulation of beta-catenin is observed at high frequency in many cancers. This accumulation correlates with either mutational activation of CTNNB1 (beta-catenin) or mutational inactivation of APC and Axin1 genes in some tumors. However, there are many tumors that display beta-catenin accumulation in the absence of a mutation in these genes. Thus, there must be additional sources for aberrant beta-catenin accumulation in cancer cells. Here, we provide experimental evidence that wild-type beta-catenin accumulates in hepatocellular carcinoma (HCC) cells in association with mutational inactivation of p53 gene. We also show that worldwide p53 and beta-catenin mutation rates are inversely correlated in HCC. These data suggest that inactivation of p53 is an important cause of aberrant accumulation of beta-catenin in cancer cells.
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PMID:P53 mutation as a source of aberrant beta-catenin accumulation in cancer cells. 1243 47

Mutations in beta-catenin are present in benign pilomatrixomas. beta-catenin is a downstream effector in the WNT-signalling pathway, acting as a signal for differentiation and proliferation. Mutations in CTNNB1, the gene encoding beta-catenin, are present in a wide variety of benign and malignant neoplasms. We examined beta-catenin in a series of pilomatrix carcinomas (15 cases) by using immunohistochemistry and DNA sequencing of exon 3 from CTNNB1, and compared these to a series of benign pilomatrixomas (13 cases). All 11 pilomatrix carcinomas available for examination showed nuclear localization of beta-catenin and mutations in exon 3 similar to those demonstrated in benign pilomatrixomas. Two of 11 pilomatrix carcinomas showed significant nuclear accumulation of p53, whereas this was absent in all 13 benign pilomatrixomas. Expression of nuclear cyclin D1 was similar in both benign pilomatrixomas and pilomatrix carcinomas. Clinical follow-up from the 15 malignant cases reported in this study and by others indicates that wide excision offers superior control of local recurrence, compared to simple excision. Immunohistochemical and molecular analysis of beta-catenin reveals that both pilomatrix carcinomas and benign pilomatrixomas harbour mutations in beta-catenin. This implies a common initial pathogenesis and is compatible with the proposition that pilomatrix carcinomas may at least on occasion arise from their benign counterparts.
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PMID:Pilomatrix carcinomas contain mutations in CTNNB1, the gene encoding beta-catenin. 1560 74

DKK1 protein belongs to a family of inhibitors of the Wnt/beta1-catenin signaling pathway. Sporadic mutations affecting almost each major player of the Wnt/beta1-catenin pathway have been described in a variety of human carcinomas. DKK1 translation can be induced by p53, thereby linking TP53 and Wnt/beta1-catenin signaling pathways. These findings raise questions in regard to human gliomas, which similar to carcinomas carry a high rate of mutations in TP53. To analyze DKK1 for its role in initiation or progression, we screened a series of 73 brain tumors for structural alterations in the entire coding sequence by single-strand conformation polymorphism and direct sequencing. While several sequence variants were detected, there were no obvious mutations affecting DKK1. Further, we analyzed the prevalence of mRNA from TP53, DKK1 and CTNNB1 and of p53 and beta1-catenin protein in a series of human gliomas with and without mutations in TP53. Transcription and expression of CTNNB1/beta1-catenin and DKK1 proved to be independent of TP53/p53. These data support in vivo function of DKK1, independent of p53, in human gliomas with no major impact on their pathogenesis.
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PMID:Mutation analysis of DKK1 and in vivo evidence of predominant p53-independent DKK1 function in gliomas. 1566 88

A considerable fraction of families with HNPCC shows no germline mismatch repair (MMR) gene mutations. We previously detected 'hidden' MMR gene defects in 42% of such families, leaving the remaining 58% 'truly' mutation negative. Here, we characterized 50 colorectal carcinomas and five adenomas arising in HNPCC families; 24 truly MMR gene mutation negative and 31 MMR gene mutation positive. Among 31 tumors from MMR gene mutation positive families, 25 (81%) had active Wnt signaling as indicated by aberrant beta-catenin localization with or without CTNNB1 mutations, compared to only 7/18 tumors from MMR gene mutation negative families (39%; P=0.005). CGH studies revealed stable profiles in 9/16 (56%) of MMR gene mutation negative tumors, which was significantly associated with membranous beta-catenin (P=0.005). Tumors with membranous beta-catenin from the MMR gene mutation negative group also showed low frequency of TP53 mutations compared to those with nuclear beta-catenin. Thus, a majority of the MMR gene mutation negative cases exhibited a novel molecular pattern characterized by the paucity of changes in common pathways to colorectal carcinogenesis. This feature distinguishes the MMR gene mutation negative families from both HNPCC families linked to MMR defects and sporadic cases, suggesting the involvement of novel predisposition genes and pathways in such families.
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PMID:Comprehensive characterization of HNPCC-related colorectal cancers reveals striking molecular features in families with no germline mismatch repair gene mutations. 1567 32

Epithelial ovarian cancer comprises the majority of malignant ovarian tumors in adult women. These neoplasms are classified into distinct morphologic categories based on the appearance of the epithelium into tumors of serous, mucinous, endometrioid, clear cell, transitional, squamous, mixed and undifferentiated type. Current data indicate that each of these histologic subtypes is associated with distinct morphologic and molecular genetic alterations: high-grade serous and possibly endometrioid carcinomas most probably arise from surface epithelial inclusion glands with TP53 mutations and dysfunction of BRCA1 and/or BRCA2; low-grade serous carcinomas probably arise in a stepwise fashion in an adenoma-borderline tumor-carcinoma sequence from typical to micropapillary borderline tumors to low-grade invasive serous carcinoma via activation of the RAS-RAF signaling pathway secondary to mutations in KRAS and BRAF; mucinous carcinomas arise via an adenoma-borderline tumor-carcinoma sequence with mutations in KRAS; low-grade endometrioid carcinomas arise from endometriosis via mutations in CTNNB1 (the gene encoding beta-catenin) and PTEN. Although the morphologic data strongly support an origin of clear cell carcinoma from endometriosis, there is limited data on the genetic alterations in these uncommon tumors. Thus it is likely that most low-grade, relatively indolent ovarian carcinomas of serous, mucinous and endometrioid type arise from pre-existing cystadenomas or endometriosis whereas most high-grade serous carcinomas arise without an easily identifiable precursor lesion.
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PMID:Origins and molecular pathology of ovarian cancer. 1576 64

An unselected series of 310 colorectal carcinomas, stratified according to microsatellite instability (MSI) and DNA ploidy, was examined for mutations and/or promoter hypermethylation of five components of the WNT signaling cascade [APC, CTNNB1 (encoding beta-catenin), AXIN2, TCF4, and WISP3] and three genes indirectly affecting this pathway [CDH1 (encoding E-cadherin), PTEN, and TP53]. APC and TP53 mutations were each present more often in microsatellite-stable (MSS) tumors than in those with MSI (P < .001 for both). We confirmed that the aneuploid MSS tumors frequently contained TP53 mutations (P < .001), whereas tumors with APC mutations and/or promoter hypermethylation revealed no associations to ploidy. Mutations in APC upstream of codons 1020 to 1169, encoding the beta-catenin binding site, were found in 15/144 mutated tumors and these patients seemed to have poor clinical outcome (P = .096). Frameshift mutations in AXIN2, PTEN, TCF4, and WISP3 were found in 20%, 17%, 46%, and 28% of the MSI tumors, respectively. More than half of the tumors with heterozygote mutations in AXIN2 were concurrently mutated in APC. The present study showed that more than 90% of all samples had alteration in one or more of the genes investigated, adding further evidence to the vital importance of activated WNT signaling in colorectal carcinogenesis.
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PMID:Genetic and epigenetic changes of components affecting the WNT pathway in colorectal carcinomas stratified by microsatellite instability. 1580 15

Ovarian cancer is the most lethal gynaecological malignancy and it most commonly occurs in postmenopausal women. Ninety per cent of ovarian cancers are derived from the ovarian surface epithelium and these neoplasms are classified into serous, mucinous, endometrioid, clear-cell and transitional-cell types. The molecular pathology of ovarian carcinomas is heterogeneous and involves various putative precursor lesions and multiple pathways of development. The most common subtype, high-grade serous carcinoma, is characterized by p53 mutations, and BRCA1 and/or BRCA2 dysfunction. It most likely arises from epithelium within inclusion cysts or from the surface of the ovary. In contrast, low-grade serous carcinomas are characterized by KRAS or BRAF mutations and appear to arise via an adenoma-borderline-carcinoma sequence. Similarly, mucinous carcinomas have KRAS mutations and probably develop via an adenoma-borderline-carcinoma sequence. Low-grade endometrioid carcinomas, however, are characterized by mutations in PTEN and CTNNB1, and microsatellite instability, and may arise from ovarian endometriosis or borderline endometrioid tumours. High-grade endometrioid carcinomas have similar changes to high-grade serous carcinomas. Clear-cell carcinomas are characterized by mutations of TGFbetaR2 and over-expression of HNF-1beta, and probably arise from ovarian endometriosis. The molecular changes in transitional-cell carcinomas of the ovary remain largely unknown. The identified molecular changes and pathways of development in epithelial ovarian cancer will facilitate the rationalized development of new diagnostic modalities and tailored therapies for this malignancy.
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PMID:Molecular pathology of epithelial ovarian cancer. 1677 56

Numerous genetic alterations are accumulated during the process of hepatocarcinogenesis. These genetic alterations can be divided into two groups. The first set of genetic alterations is specific of hepatocellular tumor risk factors. It includes integration of hepatitis B virus (HBV) DNA, R249S TP53 (tumor protein p53) mutation in aflatoxin B1-exposed patients, KRAS mutations related to vinyl chloride exposure, hepatocyte nuclear factor 1alpha (HNF1alpha) mutations associated to hepatocellular adenomas and adenomatosis polyposis coli (APC) germline mutations predisposing to hepatoblastomas. The second set of genetic alterations are etiological nonspecific, it includes recurrent gains and losses of chromosomes, alteration of TP53 gene, activation of WNT/beta-catenin pathway through CTNNB1/beta-catenin and AXIN (axis inhibition protein) mutations, inactivation of retinoblastoma and IGF2R (insulin-like growth factor 2 receptor) pathways through inactivation of RB1 (retinoblastoma 1), P16 and IGF2R. Comprehensive analyses of these genetic alterations have defined two pathways of hepatocarcinogenesis according to the presence or the absence of chromosomal instability. Hepatitis B virus and poorly differentiated tumors are related to chromosome instable tumors associated with frequent TP53 mutations, whereas non-HBV and well-differentiated tumors are related to chromosomal stable samples that are frequently beta-catenin activated. These classifications have clinical relevance as genetic alterations may also be related to prognosis.
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PMID:Genetics of hepatocellular tumors. 1679 19


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