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)

Relationships between adenomatous polyposis coli (APC) mutations, BRAF V600E mutations, and the CpG island methylator phenotype (CIMP) in colon cancer have not been explored. In addition, controversies exist about the proportion of tumors with APC mutations in the mutation cluster region (MCR); how commonly APC, Ki-ras, and p53 mutations occur in the same tumor; and whether APC mutations occur in sporadic microsatellite-unstable tumors. The APC gene was therefore sequenced in 90 colonic adenocarcinomas previously evaluated for CIMP, microsatellite instability, BRAF, Ki-ras, and p53. APC mutations were inversely related to BRAF mutations (P = 0.0003) and CIMP (P = 0.02) and directly related to p53 and Ki-ras mutations (P = 0.04). Slightly more than half of APC mutations occurred outside of the MCR, and frameshift mutations were more likely than nonsense mutations to occur in the MCR (21 of 28 versus 12 of 40, P = 0.0003). APC mutations were found in sporadic microsatellite-unstable tumors and were more likely to be frameshifts in short nucleotide repeats (P = 0.007). The occurrence of APC, Ki-ras, and p53 mutations together in the same tumor was uncommon (11.1%). In conclusion, an analysis restricted to the MCR will miss more than half of APC mutations as well as mischaracterize their mutational spectrum. The conventional wisdom that most colon cancers contain APC, Ki-ras, and p53 mutations is incorrect. Microsatellite instability may precede acquisition of APC mutations in sporadic microsatellite-unstable tumors. The relationships of APC mutations to other genetic and epigenetic alterations add to the already impressive genetic heterogeneity of colon cancer.
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PMID:APC mutations and other genetic and epigenetic changes in colon cancer. 1729 92

We have previously identified mouse DDA3 as a p53-inducible gene. To explore the functional role of DDA3, we screened a mouse brain cDNA library by the yeast two-hybrid assay, and identified the microtubule plus-end binding protein EB3 as a DDA3-interacting protein. Binding of DDA3 to EB3 was verified by glutathione S-transferase (GST) pull-down assay and subcellular colocalization; co-immunoprecipitation further indicated that interaction of these two proteins within cells required intact microtubules. Domains of DDA3-EB3 interaction were mapped by GST pull-down assay to amino acids 118-241 and 242-329 of DDA3 and the N- and C-termini of EB3. Immunofluorescence analysis revealed colocalization of DDA3 with microtubules in various cell phases, and regions encompassing aa 118-241 and 242-329 contained microtubule-interacting and bundling activities. In vitro microtubule-binding assay showed that DDA3 and EB3 associated directly with microtubules, and cooperated with each other for microtubule binding. In addition, DDA3 bound to the EB3 interacting partner adenomatous polyposis coli 2 (APC2), a homolog of the tumor suppressor APC, which is a component of the beta-catenin destruction complex. Ectopic expression of DDA3 and EB3 enhanced beta-catenin-dependent transactivation and cyclin D1 production, whereas knockdown of endogenous DDA3 or EB3 inhibited beta-catenin-mediated transactivation and the ability of cells to form colonies. Together, our results identify DDA3 as a novel microtubule-associated protein that binds to EB3, and implicate DDA3 and EB3 in the beta-catenin-mediated growth signaling.
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PMID:p53 downstream target DDA3 is a novel microtubule-associated protein that interacts with end-binding protein EB3 and activates beta-catenin pathway. 1731 Sep 96

Sporadic colon cancer is a major cause of death throughout the world. Multistage development of the disease has been associated with remarkable genetic events, mainly at the level of oncogenes and oncosuppressor genes, most notably APC (adenomatous polyposis coli), ras and p53. Despite all of these efforts, the development of a sensitive and convenient diagnostic system for detecting colorectal cancers at the early stage is still in progress. In recent years, cDNA and oligonucleotide microarray technologies have made the analysis of gene expression profiles of colorectal tumours at the genomic level possible and have identified signatures of gene expression associated with pre-cancerous phenotypes, cancers of the early stage and/or metastatic cancer. The contribution of this powerful technology in identification of novel important genes for prognosis, diagnosis and therapy of sporadic colorectal will be discussed.
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PMID:Microarray analysis to reveal genes involved in colon carcinogenesis. 1747 35

Pathways of the molecular pathogenesis of colorectal carcinoma have been extensively studied and molecular lesions during the development of the disease have been revealed. High up in the list of colorectal cancer lesions are APC (adenomatous polyposis coli), K-ras, Smad4 (or DPC4-deleted in pancreatic cancer 4) and p53 genes. All these molecules are part of important pathways for the regulation of cell proliferation and apoptosis and as a result perturbation of these processes lead to carcinogenesis. The ubiquitin-proteasome system (UPS) is comprised of a multi-unit cellular protease system that regulates several dozens of cell proteins after their ligation with the protein ubiquitin. Given that among these proteins are regulators of the cell cycle, apoptosis, angiogenesis, adhesion and cell signalling, this system plays a significant role in cell fate and carcinogenesis. UPS inhibition has been found to be a pre-requisite for apoptosis and is already clinically exploited with the proteasome inhibitor bortezomib in multiple myeloma. Cyclooxygenase-2 (Cox-2) is the inducible form of the enzyme that metabolizes the lipid arachidonic acid to prostaglandin H2, the first step of prostaglandins production. This enzyme is up-regulated in colorectal cancer and in several other cancers. Inhibition of Cox-2 by aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been found to inhibit proliferation of colorectal cancer cells and in epidemiologic studies has been shown to reduce colon polyp formation in genetically predisposed populations and in the general population. NSAIDs have also Cox-independent anti-proliferative effects. Targeted therapies, the result of increasingly understanding carcinogenesis in the molecular level, have entered the field of anti-neoplastic treatment and are used by themselves and in combination with chemotherapy drugs. Combinations of targeted drugs have started also to be investigated. This article reviews the molecular pathogenesis of colorectal cancer, the roles of UPS and Cox-2 in it and puts forward a rational for their combined inhibition in colorectal cancer treatment.
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PMID:Pathogenesis of colorectal carcinoma and therapeutic implications: the roles of the ubiquitin-proteasome system and Cox-2. 1748 76

In this study, we describe a previously uncharacterized type of adenomatous polyp of the colorectum that shows prominent, thin, elongated projections of neoplastic epithelium with a serrated contour, which we have termed "filiform serrated adenoma" (SA). Routinely processed polypectomy specimens from 18 patients with filiform SA and 23 controls with traditional (nonfiliform) SA were evaluated for their clinical and pathologic features, and immunohistochemically stained for a variety of markers (O-methylguanine methyltransferase, MLH1, MSH2, CDX2, nuclear beta-catenin, p53, and Ki-67) designed to evaluate their molecular and proliferative characteristics. DNA was extracted from the paraffin-embedded materials, amplified by polymerase chain reaction, and analyzed for microsatellite instability, BRAF, K-ras, and p53 mutational status. Five cases contained sufficient non-neoplastic tissue for dissection and DNA extraction, allowing analysis of loss of heterozygosity. The study group consisted of 7 males and 11 females of mean age 64 years (range: 42 to 89 y). All 18 filiform SAs were located in the left colon, including 15 (83%) that occurred in the rectum, compared with 43% of the control group (P=0.03). Filiform SAs were also larger (1.6 cm) than SAs (mean: 1.2 cm, P=0.02), but no other clinical differences were noted. Most (56%) filiform SAs contained marked stromal edema and tall nonmucinous cells with abundant eosinophilic cytoplasm (61%). High-grade dysplasia was present in 4/18 (22%) cases. Four (22%) filiform SAs also contained nonserrated adenomatous elements with a villous (3 cases) or tubular (1 case) growth pattern. Two (11%) cases contained adjacent areas of sessile SAs and 4 (22%) had hyperplastic areas. None of the polyps in the control group showed stromal edema, high-grade dysplasia, or mixed elements. Polyps in both groups demonstrated comparable staining patterns for O-methylguanine methyltransferase, MLH-1, MSH-2, CDX2, beta-catenin, and Ki-67, and none showed increased nuclear p53 expression. Low-frequency microsatellite instability was present in 5/12 (42%) filiform SAs, 7/12 (58%) were microsatellite stable. Mitogen-activated protein kinase pathway abnormalities were present in 71% of the cases [7/14 (50%) with BRAF and 3/14 (21%) with K-ras mutations]. Four cases showed silent p53 mutations upon direct sequencing and 4 revealed loss of heterozygosity at the loci evaluated, including 1 at D5S346 [adenomatous polyposis coli (APC) gene], 1 at D17S250 (p53 gene), and 2 at MYCL (chromosome 1p34). We conclude that filiform SA potentially represents an unusual variant of SA with a predilection for the left colon, particularly the rectum.
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PMID:Filiform serrated adenomas: a clinicopathologic and immunophenotypic study of 18 cases. 1766 49

In vitro ras activation enhances the epithelial-mesenchymal transition of colorectal carcinoma cells. But ras effects are known to be highly dependent on cell types and the tissue context. Therefore, this study was made to test the hypothesis that in clinical colorectal carcinoma specimens, aggressive invasion phenotypes, specifically tumor budding and podia formation, would correlate with K-ras gene mutations. In a series of 95 clinically sporadic primary colorectal carcinomas collected ad hoc, tumor budding and podia formation were counted using pan-cytokeratin immunohistochemistry, and K-ras gene mutations in codons 12 and 13 were determined. Consistent with the hypothesis, tumor budding and podia formation were observed to be significantly higher in the 32 (34.7%) of the tumors with K-ras gene mutations (29 mutations in codon 12, 3 in codon 13), and this correlation was observed independent of the patterns of invasion (expansive versus infiltrative). Microsatellite status, numbers of losses of heterozygosity, adenomatous polyposis coli and p53 gene mutations, and degree of promoter methylations (CIMP status) were not associated with K-ras gene mutations. Besides their effects on the tumor cell cycles, oncogenic K-ras gene mutations in colorectal carcinomas could be important for aggressive tumor invasion. This may be important in metastasizing disease and could provide a rationale for developing drugs that interrupt ras-signaling cascades.
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PMID:High-degree tumor budding and podia-formation in sporadic colorectal carcinomas with K-ras gene mutations. 1770 62

Individuals diagnosed with ulcerative colitis face a significantly increased risk of developing colorectal dysplasia and cancer during their lifetime. To date, little attention has been given to the development of a chemopreventive intervention for this high-risk population. The mouse model of dextran sulfate sodium (DSS) - induced colitis represents an excellent preclinical system in which to both characterize the molecular events required for tumor formation in the presence of inflammation and assess the ability of select agents to inhibit this process. Cyclic administration of DSS in drinking water results in the establishment of chronic colitis and the development of colorectal dysplasias and cancers with pathological features that resemble those of human colitis-associated neoplasia. The incidence and multiplicity of lesions observed varies depending on the mouse strain used (ie, Swiss Webster, C57BL/6J, CBA, ICR) and the dose (0.7%-5.0%) and schedule (1-15 cycles with or without a subsequent recovery period) of DSS. The incidence of neoplasia can be increased and its progression to invasive cancer accelerated significantly by administering DSS in combination with a known colon carcinogen (azoxymethane (AOM), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-1- methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)) or iron. More recent induction of colitis-associated neoplasia in genetically defined mouse strains has provided new insight into the role of specific genes (ie, adenomatous polyposis coli (Apc), p53, inducible nitric oxide synthase (iNOS), Msh2) in the development of colitis-associated neoplasias. Emerging data from chemopreventive intervention studies document the efficacy of several agents in inhibiting DSS-induced neoplasia and provide great promise that colitis-associated colorectal neoplasia is a preventable disease.
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PMID:Dextran sulfate sodium-induced colitis-associated neoplasia: a promising model for the development of chemopreventive interventions. 1772 78

The capacity to model cancer within the mouse has advanced significantly in recent years. Perhaps the most notable technical gains have been in the development of techniques that allow the temporal and spatial control of gene expression, so that it is now possible to regulate target genes in the tissue of choice and at a given time [Maddison and Clarke (2005) J. Pathol. 205, 181-193; Shaw and Clarke (2007) DNA Repair 6, 1403-1412; Marsh and Clarke (2007) Expert Rev. Anticancer Ther. 7, 519-531]. We have used these approaches to study tumorigenesis in the murine intestine. Loss of function of the tumour-suppressor gene Apc (adenomatous polyposis coli) has been associated with the development of both human and murine neoplasia, principally those of the intestinal epithelium. However, as Apc has been implicated in multiple cellular functions, the precise mechanisms underlying these associations remain somewhat unclear. I review here the use of an inducible strategy to co-ordinately delete genes from the adult murine epithelium. This approach has allowed a characterization of the direct consequences of inactivation of gene function. For Apc, these include failure in the differentiation programme, failure to migrate, aberrant proliferation and the aberrant induction of apoptosis. Transcriptome analysis of this model has also identified potential new targets for therapeutic intervention, such as Sparc (secreted protein acidic and rich in cysteine), deficiency of which, we have now shown, suppresses adenoma formation. Finally, we have been able to address how other genes modulate the consequences of Apc loss. Thus we show that there is little effect following loss of cyclin D1, Tcf-1 and p53, but that there are marked differences following loss of either c-Myc or Mbd2. The models therefore allow us to define the earliest events associated with carcinogenesis in the intestine.
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PMID:Cancer genetics: mouse models of intestinal cancer. 1795 46

Inflammatory bowel disease (IBD) is a gastrointestinal disorder of unknown etiology or cure. One complication of IBD is an increased risk for development of colon cancer. The aims of this study were to use a previously established rat model of colitis to develop a new model of colitis-associated colon cancer and ascertain the involvement of three cancer-related genes: K-ras, adenomatous polyposis coli (APC), and p53. Four groups of rats were used: reactivated 1,2-dimethylhydrazine [DMH; trinitrobenzene sulfonic acid (TNBS) was used to induce colitis followed by a weekly s.c. dose of DMH], prolonged reactivation (inflammation was induced with TNBS, then maintained twice a week), saline-DMH (animals received saline instead of TNBS followed by a weekly dose of DMH), and normal (received no treatment). Animals were sacrificed at 5, 10, or 15 weeks, and colon samples were taken for pathologic analysis and gene mutation detection. No dysplasia was found in the normal group. The highest incidences of dysplasia were as follows: prolonged reactivation group at 5 weeks (60%), reactivated DMH group at 10 weeks (83%), and saline-DMH group at 15 weeks (67%). Carcinoma was found in both the prolonged reactivation and saline-DMH groups. No mutations were found in the K-ras oncogene; however 62% of the APC samples (exon 15 at nucleotide 2778) and 76% of p53 (exon 6 at nucleotide 1327) showed substitutions. The prolonged reactivation group may be considered a new model of colitis-associated colon cancer, offering the potential to study cancer prevention strategies for patients with IBD.
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PMID:Prolonged chronic inflammation progresses to dysplasia in a novel rat model of colitis-associated colon cancer. 1800 20

Colon cancer arises through a multistep process involving inactivation of tumor suppressor proteins and activation of oncogene-encoded proteins. Development of colon cancer frequently involves mutation of the adenomatous polyposis coli (APC) tumor suppressor. The activity of the proto-oncogene-encoded Src tyrosine kinase is commonly elevated in colon cancer, with higher activity observed as tumors progress and metastasize. Both APC and Src are multifunctional proteins that have been implicated in the control of cell proliferation, but also as regulators of cytoskeletal changes associated with cell motility and invasion. To investigate the potential for biological cooperativity between APC partial loss-of-function and Src gain-of-function, oncogenic Src was stably expressed in mouse colon epithelial cell lines IMCE (APC(+/min)) and YAMC (APC(+/+)). Under permissive growth conditions, these lines are conditionally immortalized through inactivation of p53. Irrespective of the APC genotype or p53 status, oncogenic Src expression led to morphologic transformation associated with loss of cell-cell junctions, cytoskeletal disorganization, and acquisition of invasive properties. However IMCE cells that carry one copy of the mutant APC(min) allele exhibited increased capacity for Src-mediated anchorage-independent proliferation as compared to the YAMC cells, and this property was enhanced under permissive growth conditions. beta-catenin levels and transcriptional activity were also elevated in the Src-transformed IMCE cells. The selective Src inhibitor, AZD0530, was found to be effective in blocking both cell invasion and anchorage-independent proliferation. These findings suggest that the combined effects of elevated Src activity and APC partial loss-of-function may contribute to the growth of colon tumors.
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PMID:Src transformation of colonic epithelial cells: enhanced anchorage-independent growth in an Apc(+/min) background. 1861 32


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