Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Complex pathways exist in mammalian cells to regulate the expression and activity of oncogenes and tumor suppressor genes. Defining these regulatory pathways is an important step towards being able to interfere with tumorigenesis. Here we discuss our recent study indicating that activation of the phosphoinositide 3-kinase (PI3K) signaling pathway through inactivating mutations in PTEN or activating mutations in PIK3CA causes functional activation of p53 signaling in human cells.(1)ur data suggest that activation of p53 is a fail-safe mechanism triggered by loss of PTEN or oncogenic activation of PI3K, and furthermore, that these events provide selective pressure to mutate p53.
...
PMID:Activated PI3K signaling as an endogenous inducer of p53 in human cancer. 1732 71

In the Western world, endometrial carcinoma is the most common malignant tumour of the female genital tract and the fourth most common cancer in women after carcinomas of breast, colorectum, and lung. The annual incidence has been estimated at 10-20 per 100 000 women. In the United States, endometrial carcinoma accounts for approximately 6000 deaths per year. Two different clinicopathological subtypes are recognised: the oestrogen-related (type I, endometrioid) and the non-oestrogen related (type II, non-endometrioid). The clinicopathological differences are parallelled by specific genetic alterations, with type I showing microsatellite instability and mutations in PTEN, PIK3CA, K-Ras, and CTNNB1 (beta-catenin), and type II exhibiting p53 mutations and chromosomal instability. This article reviews the genetic changes of endometrial carcinogenesis in the light of morphological features of the tumours and their precursors.
...
PMID:Endometrial carcinoma: pathology and genetics. 1736 24

Human papilloma virus (HPV) infection is considered as an important aetiological factor for anal squamous cell carcinoma (ASCC) but is not sufficient for tumour progression. This carcinoma is poorly understood at the molecular level. Using the largest cohort of cases to date we investigated the molecular mechanisms underlying ASCC development, in particular the roles of TP53, MDM2 and AKT. Viral infection in our cohort occurred at high frequency (73%, 94/128) with HPV16 accounting for the majority (86%, 81/94) of infected cases. Only 4% (5/119) of ASCCs showed TP53 (exons 5-8) mutations, but a high frequency (91%, 100/110) of nuclear protein expression of TP53 was observed. There was a significant association (p < 0.001) between nuclear accumulation of TP53 and MDM2 protein although no MDM2 mutations were found, and copy number was normal. Cellular accumulation of phosphorylated-AKT was observed in 66% (82/125) of ASCCs and an association demonstrated between nuclear accumulation of MDM2 and activated AKT (p < 0.001). We observed a high frequency of copy number gain at PIK3CA (47%), and some coding sequence mutations (4%). Amplification of PIK3CA was associated with presence of phosphorylated-AKT (p= 0.008). There was no association between virus infection and TP53 nuclear accumulation (p = 0.5). However, a significant association was found between infection and MDM2 nuclear staining, and between infection and activated AKT (p = 0.04, p = 0.01, respectively). We propose that activation of AKT, possibly through the PI3K-AKT pathway, is an important component of ASCC tumorigenesis that contributes to MDM2 and TP53 accumulation in the nucleus.
...
PMID:Activation of AKT and nuclear accumulation of wild type TP53 and MDM2 in anal squamous cell carcinoma. 1772 20

The development of targeted therapies creates a need to discriminate tumours accurately by their histological and genetic characteristics. Here, we aim to identify gene expression profiles and single markers that recapitulate the pathological and genetic background of non-small cell lung cancer (NSCLC). We performed cDNA microarray analysis on a series of 69 NSCLCs, with known mutation status for important genes, and six normal lung tissues. Unsupervised cluster analysis segregated normal lungs from lung tumours and lung tumours according to their histopathology and the presence of EGFR mutations. Several transcripts were highly overexpressed (by approximately 20 times) in squamous cell carcinomas (SCCs) relative to adenocarcinomas (ACs) and confirmed by immunohistochemistry in an independent cohort of 75 lung tumours. Expression of 13 genes constituted the most prominent hallmarks of EGFR-mutant tumours, including increased levels of proline dehydrogenase (PRODH) and down-regulation of X-box binding protein 1 (XBP1). No genes were differentially expressed, with a fold change >or= 4 or <or=0.25 and a significance level of 5% false-discovery rate, in tumours carrying mutations of TP53 or KRAS. In addition, we organized gene expression data by the position of each gene in the chromosome and observed a cluster of highly expressed genes in chromosome 3q, including PIK3CA, that was characteristic of SCCs. FISH analysis demonstrated a strong statistically significant association between increased levels of PIK3CA expression in these tumours and gene amplification (p < 0.0001; t-test). In conclusion, histopathological phenotypes and, likely, the presence of EGFR mutations confer lung tumours with a marked pattern of gene expression. Moreover, our cDNA microarray analysis identified increased PIK3CA expression due to gene amplification in lung squamous cell carcinomas: this may represent a marker of sensitivity to therapy with PI3K inhibitors.
...
PMID:Expression signatures in lung cancer reveal a profile for EGFR-mutant tumours and identify selective PIK3CA overexpression by gene amplification. 1799 65

The occurrence of oncogenic alleles can display striking tissue specificity. For example KRAS mutations are very frequent in pancreatic cancers but relatively rare in melanomas. The opposite is true for BRAF mutations. Somatic mutations in the gene encoding for the phosphatidylinositol 3-kinase (PI3KCA) catalytic subunit, PIK3CA, occur at high frequency in many solid cancers. We have examined whether PI3K oncogenic mutations (exons 9 and 20) might exhibit gender and/or tissue specificity. By examining large cohorts of breast and colorectal cancers affecting both men and women we found that the pattern of PIK3CA mutations is distinctive. In colorectal cancers, PIK3CA (but not KRAS, APC, or TP53) mutations display a gender bias occurring at higher frequencies in women. We also found that male breast cancers display PIK3CA mutations at an overall frequency similar to that observed in female breast tumors. In male breast cancers, however, PIK3CA mutations are found mainly in exon 20. We conclude that PI3KCA mutations affecting exons 9 and 20 display gender- and tissue-specific patterns, thus suggesting that the different amino acid changes could exert distinct functional effects on the oncogenic properties of this enzyme. Furthermore, we propose that sexual dimorphisms and tissue specific factors might directly or indirectly influence the occurrence of PI3KCA cancer alleles.
...
PMID:PIK3CA cancer mutations display gender and tissue specificity patterns. 1802 11

Malignant melanoma originates in melanocytes, the pigment-producing cells of the skin and eye, and is one of the most deadly human cancers with no effective cure for metastatic disease. Like many other cancers, melanoma has both environmental and genetic components. For more than 20 years, the melanoma genome has been subject to extensive scrutiny, which has led to the identification of several genes that contribute to melanoma genesis and progression. Three molecular pathways have been found to be nearly invariably dysregulated in melanocytic tumors, including the RAS-RAF-MEK-ERK pathway (through mutation of BRAF, NRAS or KIT), the p16 INK4A-CDK4-RB pathway (through mutation of INK4A or CDK4) and the ARF-p53 pathway (through mutation of ARF or TP53). Less frequently targeted pathways include the PI3K-AKT pathway (through mutation of NRAS, PTEN or PIK3CA) and the canonical Wnt signaling pathway (through mutation of CTNNB1 or APC). Beyond the specific and well-characterized genetic events leading to activation of proto-oncogenes or inactivation of tumor suppressor genes in these pathways, systematic high-resolution genomic analysis of melanoma specimens has revealed recurrent DNA copy number aberrations as well as perturbations of DNA methylation patterns. Melanoma provides one of the best examples of how genomic analysis can lead to a better understanding of tumor biology. We review current knowledge of the genes involved in the development of melanoma and the molecular pathways in which these genes operate.
...
PMID:The genome and epigenome of malignant melanoma. 1804 49

EML4-ALK gene fusions have recently been discovered in a subset of human lung carcinomas, and fusions of the ALK tyrosine kinase gene with the NPM, TPM3, CLTC, ATIC, and TFG genes have been found in hematological malignancies. To elucidate the role of fusions between ALK and other genes in pulmonary carcinogenesis, we examined 77 non-small cell lung carcinomas (NSCLCs) for EML4-, NPM-, TPM3-, CLTC-, ATIC-, and TFG-ALK fusion transcripts by RT-PCR and subsequent sequencing analysis. Although no expression of NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts were detected in any of the cases, expression of EML4-ALK fusion transcripts was detected in two (2.6%) of the 77 NSCLCs. In one of the two NSCLCs there was fusion between exon 13 of EML4 and exon 20 of ALK, i.e., variant 1, and in the other there was fusion between exon 20 of EML4 and exon 20 of ALK, i.e., variant 2. Both patients had a history of smoking, and histologically the carcinomas were adenocarcinoma. No somatic mutations were detected in the mutation cluster regions of the EGFR, K-RAS, and PIK3CA genes in these two carcinomas, however, a Pro177Ser mutation of the p53 gene was detected in the carcinoma that contained the variant 1 EML4-ALK fusion transcripts. In situ PCR of a paraffin block section showed that the carcinoma with expression of the variant 1 actually contained an EML4-ALK fusion gene. These results suggested that the EML4-ALK fusion gene product is involved in the carcinogenesis of a subset of NSCLCs.
...
PMID:EML4-ALK fusion transcripts, but no NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts, in non-small cell lung carcinomas. 1824 62

Inactivation of the transcription factor and tumor suppressor p53, and overexpression or mutational activation of PIK3CA, which encodes the p110alpha catalytic subunit of phosphatidylinositol-3-kinase (PI3K), are two of the most common deleterious genomic changes in cancer, including in ovarian carcinomas. We investigated molecular mechanisms underlying interactions between these two mediators and their possible roles in ovarian tumorigenesis. We identified two alternate PIK3CA promoters and showed direct binding of and transcriptional inhibition by p53 to one of these promoters. Conditional suppression of functional p53 increased p110alpha transcripts, protein levels and PI3K activity in immortalized, non-tumorigenic ovarian surface epithelial (OSE) cells, the precursors of ovarian carcinoma. Conversely, overexpression of p53 by adenoviral infection and activation of p53 by gamma-irradiation both diminished p110alpha protein levels in normal OSE and ovarian cancer cells. The demonstration that p53 binds directly to the PIK3CA promoter and inhibits its activity identifies a novel mechanism whereby these two mediators regulate cellular functions, and whereby inactivation of p53 and subsequent upregulation of PIK3CA might contribute to the pathophysiology of ovarian cancer.
...
PMID:Mechanisms underlying p53 regulation of PIK3CA transcription in ovarian surface epithelium and in ovarian cancer. 3291 31

Analysis of recurrent DNA amplification can lead to the identification of cancer driver genes, but this process is often hampered by the low resolution of existing copy number analysis platforms. Fifty-one breast tumors were profiled for copy number alterations (CNAs) with the high-resolution Affymetrix 500K SNP array. These tumors were also expression-profiled and surveyed for mutations in selected genes commonly mutated in breast cancer (TP53, CDKN2A, ERBB2, KRAS, PIK3CA, PTEN). Combined analysis of common CNAs and mutations revealed putative associations between features. Analysis of both the prevalence and amplitude of CNAs defined regions of recurrent alteration. Compared with previous array comparative genomic hybridization studies, our analysis provided boundaries for frequently altered regions that were approximately one-fourth the size, greatly reducing the number of potential alteration-driving genes. Expression data from matched tumor samples were used to further interrogate the functional relevance of genes located in recurrent amplicons. Although our data support the importance of some known driver genes such as ERBB2, refined amplicon boundaries at other locations, such as 8p11-12 and 11q13.5-q14.2, greatly reduce the number of potential driver genes and indicate alternatives to commonly suggested driver genes in some cases. For example, the previously reported recurrent amplification at 17q23.2 is reduced to a 249 kb minimal region containing the putative driver RPS6KB1 as well as the putative oncogenic microRNA mir-21. High-resolution copy number analysis provides refined insight into many breast cancer amplicons and their relationships to gene expression, point mutations and breast cancer subtype classifications. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.
...
PMID:High-resolution genomic and expression analyses of copy number alterations in breast tumors. 1833 99

Somatic PIK3CA mutations are often present in colorectal cancer. Mutant PIK3CA activates AKT signaling, which up-regulates fatty acid synthase (FASN). Microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) are important molecular classifiers in colorectal cancer. However, the relationship between PIK3CA mutation, MSI and CIMP remains uncertain. Using Pyrosequencing technology, we detected PIK3CA mutations in 91 (15%) of 590 population-based colorectal cancers. To determine CIMP status, we quantified DNA methylation in eight CIMP-specific promoters [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1] by real-time polymerase chain reaction (MethyLight). PIK3CA mutation was significantly associated with mucinous tumors [P = .0002; odds ratio (OR) = 2.44], KRAS mutation (P < .0001; OR = 2.68), CIMP-high (P = .03; OR = 2.08), phospho-ribosomal protein S6 expression (P = .002; OR = 2.19), and FASN expression (P = .02; OR = 1.85) and inversely with p53 expression (P = .01; OR = 0.54) and beta-catenin (CTNNB1) alteration (P = .004; OR = 0.43). In addition, PIK3CA G-to-A mutations were associated with MGMT loss (P = .001; OR = 3.24) but not with MGMT promoter methylation. In conclusion, PIK3CA mutation is significantly associated with other key molecular events in colorectal cancer, and MGMT loss likely contributes to the development of PIK3CA G>A mutation. In addition, Pyrosequencing is useful in detecting PIK3CA mutation in archival paraffin tumor tissue. PIK3CA mutational data further emphasize heterogeneity of colorectal cancer at the molecular level.
...
PMID:PIK3CA mutation in colorectal cancer: relationship with genetic and epigenetic alterations. 1851 90


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

---