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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The epidermal growth factor receptor (EGFR) gene has recently been reported to be mutated in a subset of non-small cell lung cancers (NSCLC), with the mutations being correlated with the patients' drug sensitivity to gefitinib, an EGFR kinase inhibitor. In this study, we searched for EGFR mutations in patients with lung cancer using primary tumor specimens obtained at initial surgery and examined whether their recurrent tumors showed a response to gefitinib depending on the presence of the activating mutation. Among 12 lung cancers that were treated with gefitinib after recurrence, we found that all four tumors which showed a response to gefitinib had an activating mutation in EGFR, whereas none of the remaining eight tumors had a mutation. Southern blot analysis showed that two of the four responsive tumors had the EGFR gene amplification. We also examined another 73 NSCLC specimens (47 males and 26 females; 53 adenocarcinomas and 20 non-adenocarcinomas) which were not treated with gefitinib to determine whether NSCLCs with an EGFR mutation have different clinicopathological properties and/or unique genetic alterations of the other cancer-associated genes. We found that 13 (18%) of 73 tumors had a mutation of the EGFR gene, with the most being detected in female adenocarcinomas. Comparing the alterations in KRAS and P53 with the EGFR mutation, we found that 10 tumors with the KRAS mutation did not have an EGFR mutation, suggesting that each mutation occurs exclusively during the development of lung cancer. These results suggest that the mutation analysis of the EGFR gene using the specimens obtained at surgery might be useful in selecting the appropriate treatment(s) for recurrent lung cancer patients.
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PMID:Mutations of epidermal growth factor receptor of non-small cell lung cancer were associated with sensitivity to gefitinib in recurrence after surgery. 1614 Apr 20

There is significant evidence supporting the hypotheses that lifestyle, diet, and bioactive components in foods are important modifiers of cancer risk. However, our ability to assess host response noninvasively is limited. To overcome this, we have developed a technology to isolate several million viable exfoliated somatic colonic cells from a small sample of stool (0.5-1.0 g) by a procedure known as somatic cell sampling and recovery (SCSR). Orally administered carotenoids appear in these cells several days after consuming the supplement, usually showing a peak concentration between 5-7 d after their ingestion. The time lag observed for the appearance of orally administered carotenoids in SCSR cells corresponds to the turnover rate of the colonic mucosa. This is an example of how changes in cell turnover rates can be carefully assessed using the SCSR system. The specific mechanisms by which individual constituents of diet affect the cancer process are not fully understood. However, host response to dietary constituents may be investigated, noninvasively, by following the modulation of tumor-associated molecular markers in these exfoliated SCSR cells. We have demonstrated the feasibility of using SCSR cells to detect the expression of carcinoembryonic antigen, CD44, and its splice variants, c-myc, c-erbb2, and mutations in the p53 gene. In this regard, SCSR cells are a readily available surrogate cellular target that may serve to monitor changes in cell turnover, differentiation, and expression of cancer-associated biomarkers that are likely to be modulated by bioactive food components.
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PMID:Exfoliated colonic epithelial cells: surrogate targets for evaluation of bioactive food components in cancer prevention. 1625 37

The mutations C742T, G746T, G747T in the TP53 gene and G35T in the KRAS gene have been repeatedly found in sectors of human tumors by direct DNA sequencing. The mutation G508A in the HPRT1 gene has been repeatedly found among peripheral T lymphocytes by clonal expansion under selective conditions. To discover if these mutations also occur frequently in normal tissues from which tumors arise, we have developed and validated allele-specific mismatch amplification mutation assays (MAMA) for each mutation. Reconstruction experiments demonstrated linearity in the range of 9-3000 mutant alleles among 3 x 10(6) wild-type alleles. The cumulative distributions of all negative controls established robust detection limits (P<0.05) of 34-125 mutants per 10(6) copies assayed depending on the mutation. One hundred and seventy-seven micro-anatomical samples of approximately (0.5-6)x10(6) tracheal-bronchial epithelial cells from nine non-smokers were assayed representing en toto the equivalent of approximately 1.6 human bronchial trees to the fifth bifurcation. Statistically significant mutant copy numbers were found in 257 of 463 assays. Clusters of mutant copies ranged from 10 to 1000 in 239/257 positive samples. As all five point mutations were detected at mutant fractions of >10(-5) in two or more lungs, we infer that they are mutational hotspots generated in lung epithelial stem cells. As the cancer-associated mutations did not differ in cluster size distribution from the HPRT1 mutation, we infer that none of the mutations conferred a growth advantage to somatic heterozygous clusters or maintenance turnover units. Specific mutants appeared in very large copy numbers, 1000-35,000, in 18/257 positive assays. Various hypotheses to account for the observed cluster size distributions are offered.
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PMID:Distributions of five common point mutants in the human tracheal-bronchial epithelium. 1645 30

Human tumor suppressor p53 is a sequence-specific master regulatory transcription factor that targets response elements (REs) in many genes. p53 missense mutations in the DNA-binding domain are often cancer associated. As shown with systems based on the yeast Saccharomyces cerevisiae, p53 mutants can alter the spectra and intensities of transactivation from individual REs. We address directly in human cells the relationship between changes in the p53 master regulatory network and biological outcomes. Expression of integrated, tightly regulated DNA-binding domain p53 mutants resulted in many patterns of apoptosis and survival following UV or ionizing radiation, or spontaneously. These patterns reflected changes in the spectra and activities of target genes, as demonstrated for P21, MDM2, BAX, and MSH2. Thus, as originally proposed for "master genes of diversity," p53 mutations in human cells can differentially influence target gene transactivation, resulting in a variety of biological consequences which, in turn, might be expected to influence tumor development and therapeutic efficacy.
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PMID:The biological impact of the human master regulator p53 can be altered by mutations that change the spectrum and expression of its target genes. 1650 5

Progression of human malignancies is accompanied by vascular events, such as formation and remodeling of blood vessels and systemic coagulopathy. Though long appreciated as comorbidity of cancer (Trousseau syndrome), vascular involvement is increasingly recognized as a central pathogenetic mechanism of tumor growth, invasion and metastasis. The major outstanding question in relation to this role has been, whether vascular perturbations are simply a reaction to the conditions of the tumor microenvironment, or are linked to the known genetic lesions causal for the onset and progression of malignancy. In this regard, we have previously hypothesized, and recently demonstrated experimentally that deregulation of certain hemostatic mechanisms, namely upregulation of tissue factor (TF) and possibly other changes (e.g. expression of thrombin receptor - PAR-1) are controlled by cancer-associated oncogenic events, such as activation of K-ras, epidermal growth factor receptor (EGFR), or inactivation of the p53 tumor suppressor gene in various human cancer cells. It appears that these respective transforming alterations exert their impact on both, cell-associated and soluble/circulating (microvesicle- associated) TF, i.e. may cause a systemic hypercoagulable state. Other genes, which more recently emerged as regulators of cancer coagulopathy include: PML-RARalpha, PTEN, and MET. While the spectrum of procoagulant targets of these genes may vary somewhat it includes: TF, PAI-1, COX-2 and possibly other hemostatic proteins. It is noteworthy that these prothrombotic changes may impact the malignant process directly (e.g. stimulate angiogenesis, tumor growth or metastasis) as a consequence of both coagulation-dependent and -independent effects. The latter are mostly related to cellular signaling events and changes in gene expression which are now known to be induced by the TF/FVIIa/Xa complex, thrombin and PARs, expressed on the surface of cancer cells, as well as tumor-associated endothelium. Interestingly, certain anticoagulants possess antimetastatic and anticancer properties (e.g. LMWH), an observation that further suggests that hypercoagulability may act as an effector mechanism of genetically driven tumor progression. Conversely, we suggest that oncogene-directed (targeted) anticancer agents could, at least in some cases, ameliorate not only cellular transformation itself, but also some of the chronic components of the cancer-related coagulopathy, something that may be relevant to therapeutic efficacy of these drugs. We also postulate that since TF is the oncogene target, circulating TF (microparticles) could serve as surrogate marker of the biological activity oncogene-directed agents exert in vivo. Thus, both genetic and epigenetic factors appear to conspire to activate various components of the hemostatic system in cancer patients, both locally and systemically. These activities act as mediators of cancer coagulopathy, angiogenesis, metastasis and other events involved in disease progression and should be recognized in designing better anticancer therapies.
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PMID:Genetic determinants of cancer coagulopathy, angiogenesis and disease progression. 1663 63

Tetraploidy can result in cancer-associated aneuploidy. As shown here, freshly generated tetraploid cells arising due to mitotic slippage or failed cytokinesis are prone to undergo Bax-dependent mitochondrial membrane permeabilization and subsequent apoptosis. Knockout of Bax or overexpression of Bcl-2 facilitated the survival of tetraploid cells at least as efficiently as the p53 or p21 knockout. When tetraploid cells were derived from diploid p53 and Bax-proficient precursors, such cells exhibited an enhanced transcription of p53 target genes. Tetraploid cells exhibited an enhanced rate of spontaneous apoptosis that could be suppressed by inhibition of p53 or by knockdown of proapoptotic p53 target genes such as BBC3/Puma, GADD45A and ferredoxin reductase. Unexpectedly, tetraploid cells were more resistant to DNA damaging agents (cisplatin, oxaliplatin and camptothecin) than their diploid counterparts, and this difference disappeared upon inhibition of p53 or knockdown of p53-inducible ribonucleotide reductase. Tetraploid cells were also more resistant against UVC and gamma-irradiation. These data indicate the existence of p53-dependent alterations in apoptosis regulation in tetraploid cells.
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PMID:Apoptosis regulation in tetraploid cancer cells. 1667 48

Infection of Hepatitis B Virus (HBV) is a risk factor of chronic active hepatitis (CAH), hepatic cirrhosis and hepatocellular carcinoma (HCC). Infection of HBV may develop to HCC without antecedent hepatic cirrhosis. Pathogenesis of HBV causing malignant changes has not been fully understood. HBx, a protein of HBV, is an activator of transcription process involved in hepatocarcinogenesis. Most of human cancer associated with mutation of p53, a Tumor Suppressor Genes, a protein serves as cellular protection for growth and cell division, which is one of predisposition factor of hepatocarcinoma. Some studies indicate the correlation between mutation / inactivation of p53 and HBV protein x (HBx) in hepatocarcinogenesis. In that process, HBx will suppress p53 function, which will lead to ineffective liver cell division and resulting in HCC.
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PMID:Hepatocarcinogenesis in viral Hepatitis B infection: the role of HBx and p53. 1695 33

The cellular E3 ubiquitin ligase E6AP (UBE3A) interacts with the cancer-associated HPV E6 oncoproteins, where together with the viral E6 oncoprotein it binds and targets the degradation of the p53 tumor suppressor. We find that the HPV-11E6 protein also associates with E6AP in vivo, and thereby can target the degradation of an E6-associated protein. Mutation of an E6-binding LXXLL peptide motif on E6AP eliminated the association, revealing a common mode of interaction between high- and low-risk E6 proteins and E6AP. E6AP was required for the in vivo degradation of DLG1 by both HVP-18 E6 and a chimeric HPV-11E6. The common functional interaction of both cancer-associated and non-cancer-associated E6 proteins with E6AP establishes a common mechanism for E6 proteins trophic to mucosal squamous epithelium.
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PMID:Association of E6AP (UBE3A) with human papillomavirus type 11 E6 protein. 1702 19

Epithelial-stromal interactions play a critical role in tumor initiation and progression; cancer-associated stroma, but not normal stroma, is known to be tumor-promoting. However, the molecular signal used by epithelial cancer cells to reprogram normal stroma to a tumorigenic stroma is not known. Here, we present evidence to suggest that the chemokine growth-regulated oncogene 1 (Gro-1) may be one such signaling molecule. We showed that the expression of Gro-1 is activated by RAS and is vital for cell survival and the malignant transformation of ovarian epithelial cells. Surprisingly, we found that Gro-1 is a potent inducer of senescence in stromal fibroblasts and that this effect depends on functional p53. Senescent fibroblasts induced by Gro-1 can promote tumor growth whereas abrogation of senescence through immortalization results in loss of such tumor promoting activity. We also demonstrated that stromal fibroblasts adjacent to epithelial cancer cells are senescent in human ovarian cancer specimens and in heterografts from RAS-transformed human ovarian epithelial cells and ovarian cancer cells. Moreover, Gro-1 was expressed at significantly higher amounts in ovarian cancer than in normal tissues and was higher in serum samples from women with ovarian cancer than in serum from women without ovarian cancer. These findings provide strong evidence that RAS-induced Gro-1 can reprogram the stromal microenvironment through the induction of senescence of fibroblasts and thus can promote tumorigenesis. Therefore, Gro-1 may be a therapeutic target as well as a diagnostic marker in ovarian cancer.
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PMID:The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. 1706 Jun 21

The p53-inhibitory function of the oncoprotein MDM2 is regulated by a number of MDM2-binding proteins, including ARF and ribosomal proteins L5, L11, and L23, which bind the central acidic domain of MDM2 and inhibit its E3 ubiquitin ligase activity. Various human cancer-associated MDM2 alterations targeting the central acidic domain have been reported, yet the functional significance of these mutations in tumor development has remained unclear. Here, we show that cancer-associated missense mutations targeting MDM2's central zinc finger disrupt the interaction of MDM2 with L5 and L11. We found that the zinc finger mutant MDM2 is impaired in undergoing nuclear export and proteasomal degradation as well as in promoting p53 degradation, yet retains the function of suppressing p53 transcriptional activity. Unlike the wild-type MDM2, whose p53-suppressive activity can be inhibited by L11, the MDM2 zinc finger mutant escapes L11 inhibition. Hence, the MDM2 central zinc finger plays a critical role in mediating MDM2's interaction with ribosomal proteins and its ability to degrade p53, and these roles are disrupted by human cancer-associated MDM2 mutations.
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PMID:Cancer-associated mutations in the MDM2 zinc finger domain disrupt ribosomal protein interaction and attenuate MDM2-induced p53 degradation. 1711 89


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