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

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Query: UMLS:C0596263 (carcinogenesis)
64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Iron (Fe) chelators induce a G1/S arrest and several of these are undergoing clinical trials as anticancer agents. Despite this, little is known concerning the precise function of Fe in cell cycle progression and the role of p53 in this process. The aim of this study was to assess the effect of Fe chelators on p53 and the mechanism involved in the chelator-mediated increase in mRNA levels of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1. Cells were incubated with the potent Fe chelator 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) and the results compared with those from cells treated with actinomycin D (Act D), which induces p53. Following incubation with 311, a 3- to 5-fold increase in nuclear p53 protein was observed in cells with wild-type p53. In addition, 311 increased p53 DNA-binding activity 2-fold, while Act D increased it 3- to 5-fold in cells with native p53. To determine the role of p53 in WAF1 transcription, a reporter construct was used consisting of a WAF1 promoter containing the p53-binding site. In cells with wild-type p53, chelators had no effect on luciferase activity, while the positive control, Act D, caused a significant increase. Hence, despite increased p53 protein expression and p53 DNA-binding activity following chelation, these latter results suggested it had no role in up-regulating WAF1 mRNA. Our experiments demonstrated: (i) that the elevated WAF1 mRNA expression after Fe chelation was due to increased transcription and also to a post-transcriptional mechanism that was sensitive to cycloheximide; and (ii) that Fe-chelation increased WAF1 expression through a p53-independent pathway.
Carcinogenesis 2003 Oct
PMID:The effect of potent iron chelators on the regulation of p53: examination of the expression, localization and DNA-binding activity of p53 and the transactivation of WAF1. 1286 19

Helicobacter pylori infection is associated with increased gastric epithelial cell turnover and is a risk factor for noncardia gastric cancer. H. pylori reduces the expression of p27 protein, a cyclin-dependent kinase inhibitor of the G(1) to S-phase cell cycle transition and gastric tumor suppressor gene. Although cell cycle dysregulation associated with decreased p27 may contribute to gastric carcinogenesis, how H. pylori reduces p27 in gastric epithelial cells remains unknown. In the present study, we investigated the mechanisms of the p27 decrease, using AGS and MKN28 gastric epithelial cells cocultured with H. pylori strains under conditions of defined cell cycle distribution. The expression of p27 protein was reduced by H. pylori in a dose- and time-dependent manner. Northern blot and pulse-chase analyses revealed that this reduction was not regulated at a transcriptional level but by accelerated p27 degradation via a proteasome-dependent pathway. Despite up-regulation of the proteasome-dependent degradation of p27 protein, neither threonine 187-phosphorylated p27 nor skp2 (the ubiquitin ligase for p27) were increased. Furthermore, H. pylori impaired p27 ubiquitination and did not increase global proteasomal function. These results indicate that H. pylori increases the degradation of p27 through a proteasomal pathway distinct from the physiological pathway that degrades p27 during cell cycle progression. Putative virulence genes of H. pylori (cagA, cagE, or vacA) played no role in reducing p27 expression. Increased degradation of p27 by H. pylori through a proteasome-dependent, ubiquitin-independent pathway may contribute to the increased risk of gastric cancer associated with chronic H. pylori infection.
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PMID:Helicobacter pylori increases proteasome-mediated degradation of p27(kip1) in gastric epithelial cells. 1290 57

The cyclin-dependent kinase inhibitor, p27, has been shown to mediate cell growth arrest thereby significantly reducing the percentage of proliferating cells. It seems that p27 expression is essential for the control of normal endometrial proliferation, and reduced or absent p27 expression may be an important step in endometrial carcinogenesis. Our aim was to demonstrate the effects of tamoxifen therapy on the expression of p27 protein in the endometrium of postmenopausal breast cancer patients. Fifty-three pre- and post-tamoxifen treatment endometrium samples were examined immunohistochemically using p27 antibody. Tamoxifen therapy (20 mg/day) for 60 days increased the expression of p27 protein in the endometrium of postmenopausal breast cancer patients. We conclude that tamoxifen therapy does not seem to be directly involved in the carcinogenesis of endometrial carcinoma since the expression of p27 is not decreased.
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PMID:Effects of tamoxifen therapy on the expression of p27 protein in the endometrium of women with primary breast cancer. 1461 25

Heavy metals like CrVI, CdII, PbII and SnII have many applications in industry. They also represent a group of labour pollutants, as they are involved in several physiological disorders, such as carcinogenesis and various tissue dysfunctions. However, limited knowledge exists regarding their effects on ageing. In the current work we provide evidence that workers chronically exposed to CrVI have considerably reduced serum levels of the biomarker of senescence and cell survival, Apolipoprotein J/Clusterin (ApoJ/CLU). Moreover, we have found that both the degree and the time of exposure to CrVI associate negatively with ApoJ/CLU serum levels. To further examine whether CrVI directly affects cellular senescence we treated for 10 weeks two adult skin fibroblasts cultures as well as embryonic fibroblasts with a range of CrVI concentrations that approximate the values recorded in the blood circulation of exposed workers. Cellular treatment with a CrVI concentration that approximates the highest concentration in the blood was extremely toxic and nearly all cells died immediately after the first treatment. Interestingly, continuous treatment with a 10-fold lower CrVI concentration resulted in the induction of premature senescence. More specifically, treated cells were growth arrested, acquired an irregular shape, were positive to beta-galactosidase staining, accumulated oxidized proteins and over-expressed the cyclin-dependent kinase inhibitor p21 and ApoJ/CLU. Similar treatments with three additional labour pollutants resulted in the induction of premature senescence by CdII, but not by SnII or PbII. In summary, our results indicate that exposure to CrVI induces alterations of senescence biomarkers both in vivo and in vitro. They also provide new valuable tools for monitoring CrVI cytotoxic effects in vivo as well as for re-evaluating the maximum permissive values of some labour pollutants, like CrVI and CdII.
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PMID:Alterations of senescence biomarkers in human cells by exposure to CrVI in vivo and in vitro. 1523 67

Helicobacter pylori infection is associated with increased gastric epithelial cell turnover and non-cardia gastric cancer. Cell cycle progression is dependent on the proteasomal degradation of p27, a cyclin-dependent kinase inhibitor and gastric tumor suppressor, following ubiquitination mediated by Skp2. c-Myc is a transcriptional repressor of p27 and also a target of Skp2. In vitro, H. pylori decreases p27 protein post-translationally. We aimed to determine how p27 is regulated by H. pylori in vivo. The effect of eradicating H. pylori on gastric epithelial p27, Skp2, and c-Myc proteins and mRNA was investigated in 22 patients with chronic gastritis, by immunohistochemistry and laser capture microdissection. The percentage of gastric antral epithelial cells expressing p27 protein was significantly higher after eradication of H. pylori (mean+/-s.e.m. 37+/-2.4% pre-eradication vs 55+/-2.8% post-eradication; P<0.001), while Skp2 and c-Myc protein-expressing cells were lower (Skp2: 35+/-3.8 vs 23+/-2.6%, P=0.009; c-Myc: 47+/-3.6 vs 30+/-3.8%, P<0.001). mRNA expressions of p27, Skp2, and c-Myc (normalized for 18SrRNA) were not changed by H. pylori eradication. H. pylori increases c-Myc and decreases gastric epithelial p27 protein expression in association with increased expression of Skp2, the regulator of p27's ubiquitin ligase complex. H. pylori may influence cell cycle progression and carcinogenesis through post-translational effects on specific gene expression.
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PMID:Altered expression of Skp2, c-Myc and p27 proteins but not mRNA after H. pylori eradication in chronic gastritis. 1611 28

Long-term exposure to synthetic and endogenous estrogens has been associated with the development of cancer in several tissues. One potential mechanism of estrogen carcinogenesis involves catechol formation and these catechols are further oxidized to electrophilic/redox active o-quinones, which have the potential to both initiate and promote the carcinogenic process. 4-Hydroxyequilenin (4-OHEN), a major phase I metabolite of several estrogens present in Premarin, is considerably more cytotoxic, carcinogenic, and mutagenic as compared to the catechol estrogen metabolites of endogenous estrogens. Previously, we showed that 4-OHEN autoxidized to an o-quinone and caused a variety of damage to DNA. Allowing more time between the induction of DNA damage and the entry of a damaged cell into the DNA synthetic phase of the cell cycle protects that cell from mutagenesis. Central to this response is the establishment of a G1 checkpoint. This checkpoint is mediated by the cyclin-dependent kinase inhibitor p21WAF1, a direct downstream target for transcriptional activation by p53. In this study, we investigated this signaling pathway. Surprisingly, exposure of the human MCF-10A immortalized nontransformed mammary epithelial cell line to 4-OHEN did not induce a p53-induced G1 arrest. A 24 h treatment with 4-OHEN significantly induced p53 and p21WAF1 protein expression at 10 and 20 microM, as well as significantly induced the transactivation of a p53-luciferase reporter gene at 20 microM. Significant decreases in cell proliferation were also observed with concentrations of 5 microM and higher of 4-OHEN. However, 4-OHEN did not induce a G1 checkpoint and cells with damaged DNA accumulated in the S phase. This S phase delay could be beneficial for the survival of the damaged cells which could contribute to the carcinogenic process.
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PMID:Response of human mammary epithelial cells to DNA damage induced by 4-hydroxyequilenin: Lack of p53-mediated G1 arrest. 1673 Jun 88

The development and progression of malignancies is a complex multistage process that involves the contribution of a number of genes giving growth advantage to cells when transformed. The role of transforming growth factor-beta (TGF-beta) in carcinogenesis is complex with tumor-suppressor or prooncogenic activities depending on the cell type and the stage of the disease. We have previously reported the identification of a novel WD-domain protein, STRAP, that associates with both TGF-beta receptors and that synergizes with the inhibitory Smad, Smad7, in the negative regulation of TGF-beta-induced transcription. Here, we show that STRAP is ubiquitously expressed and is localized in both cytoplasm and nucleus. STRAP is up-regulated in 60% colon and in 78% lung carcinomas. Stable expression of STRAP results in activation of mitogen-activated protein kinase/extracellular signal-regulated kinase pathway and in down-regulation of the cyclin-dependent kinase inhibitor p21(Cip1), which results in retinoblastoma protein hyperphosphorylation. In addition, we have observed that Smad2/3 phosphorylation, TGF-beta-mediated transcription, and growth inhibition are induced in STRAP-knockout mouse embryonic fibroblasts compared with wild-type cells. Ectopic expression of STRAP in A549 lung adenocarcinoma cell line inhibits TGF-beta-induced growth inhibition and enhances anchorage-independent growth of these cells. Moreover, overexpression of STRAP increases tumorigenicity in athymic nude mice. Knockdown of endogenous STRAP by small interfering RNA increases TGF-beta signaling, reduces ERK activity, increases p21(Cip1) expression, and decreases tumorigenicity. Taken together, these results suggest that up-regulation of STRAP in human cancers may provide growth advantage to tumor cells via TGF-beta-dependent and TGF-beta-independent mechanisms, thus demonstrating the oncogenic function of STRAP.
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PMID:Oncogenic function of a novel WD-domain protein, STRAP, in human carcinogenesis. 1677 89

Colorectal cancer (CRC) is the most common gastrointestinal malignancy. Most of the clinical data on CRC prevention have come from the use of aspirin. Besides inhibition of cyclooxygenases, aspirin has a diversity of molecular effects that counteract colon carcinogenesis. Aspirin restrains cell proliferation by inducing a G1 arrest in colorectal cells. To determine which cell cycle checkpoint pathways are involved in this response, colorectal cell lines wild-type or defective for p53 and p21Waf1/Cip1 were treated with aspirin or the anti-proliferative drug sulindac sulfide, then assayed for proliferative activity, for cell cycle progression and apoptosis, for the activation and phosphorylation of checkpoint components and for the transcriptional up-regulation of p21Waf1/Cip1 and Bax. Aspirin and sulindac sulfide induced a G1 arrest within 48 h. While all cell lines responded in a comparable way to sulindac sulfide, the aspirin-induced G1 arrest was dependent on p21Waf1/Cip1--as cells lacking the cyclin-dependent kinase inhibitor failed to show this arrest--and on ataxia-telangiectasia-mutated kinase (ATM)--as the inhibitor caffeine abrogated the checkpoint. Moreover, aspirin induced cell death mainly in cells expressing p53. Aspirin induced the phosphorylation of p53 at residue Ser15 within 8 h in a caffeine-dependent manner, and also caused the activation of checkpoint kinase 2 and the cleavage of caspase 7. Our results suggest that aspirin induces a G1 arrest and apoptosis by activating p53 and p21Waf1/Cip1 in an ATM-dependent way. By activating these checkpoint pathways, aspirin may restrain uncontrolled proliferation of colorectal cells, enhance their response to stresses such as DNA damage and promote entry of abnormal cells into apoptosis.
Carcinogenesis 2007 Oct
PMID:Aspirin blocks proliferation in colon cells by inducing a G1 arrest and apoptosis through activation of the checkpoint kinase ATM. 1751 82

MUC4 is a transmembrane mucin expressed in pancreatic ductal adenocarcinoma (DAC) in contrast to normal pancreas, and is an independent predictor of poor prognosis in patients with invasive DAC. Our aim was therefore to investigate the mechanisms that control MUC4 expression in pancreatic cancer cells. We focused our study on activator protein (AP)-2alpha transcription factor that acts as a tumour suppressor gene in several cancers. In a series of 18 human DAC, using immunohistochemistry, we confirmed that MUC4 was exclusively expressed in cancerous or preneoplastic lesions in 83% of the samples. On the contrary, AP-2 was mainly expressed by non-tumoural ductal cells (61%) or endocrine cells (67%). Moreover, MUC4 and AP-2 were never found co-expressed suggesting an inhibitory role of AP-2alpha in normal ductal cells. In CAPAN-1 and CAPAN-2 cells, transient AP-2alpha over-expression decreased both MUC4 mRNA and apomucin levels by 20-40% by a mechanism involving inhibition of MUC4 promoter. By chromatin immunoprecipitation and gel-shift assays, we demonstrated that this inhibition involved two AP-2 cis-elements located in the -475/-238 region of the promoter. CAPAN-1 clones, which stably over-expressed AP-2alpha, displayed a strong MUC4 down-regulation (-38 to -100%), a significant decrease of both cell proliferation and invasion concomitant to the up-regulation of p27 cyclin-dependent kinase inhibitor. In conclusion, our data provide evidence that AP-2alpha is an important in vivo negative regulator of MUC4 expression in human pancreatic tissue and that AP-2alpha may play a tumour-suppressive role in pancreatic DAC.
Carcinogenesis 2007 Nov
PMID:Transcription factor AP-2alpha represses both the mucin MUC4 expression and pancreatic cancer cell proliferation. 1762 92

Tumour suppressor genes (TSGs) inhibiting normal cellular growth are frequently silenced epigenetically in cancer. DNA methylation is commonly associated with TSG silencing, yet mutations in the DNA methylation initiation and recognition machinery in carcinogenesis are unknown. An intriguing possible mechanism for gene regulation involves widespread non-coding RNAs such as microRNA, Piwi-interacting RNA and antisense RNAs. Widespread sense-antisense transcripts have been systematically identified in mammalian cells, and global transcriptome analysis shows that up to 70% of transcripts have antisense partners and that perturbation of antisense RNA can alter the expression of the sense gene. For example, it has been shown that an antisense transcript not naturally occurring but induced by genetic mutation leads to gene silencing and DNA methylation, causing thalassaemia in a patient. Here we show that many TSGs have nearby antisense RNAs, and we focus on the role of one RNA in silencing p15, a cyclin-dependent kinase inhibitor implicated in leukaemia. We found an inverse relation between p15 antisense (p15AS) and p15 sense expression in leukaemia. A p15AS expression construct induced p15 silencing in cis and in trans through heterochromatin formation but not DNA methylation; the silencing persisted after p15AS was turned off, although methylation and heterochromatin inhibitors reversed this process. The p15AS-induced silencing was Dicer-independent. Expression of exogenous p15AS in mouse embryonic stem cells caused p15 silencing and increased growth, through heterochromatin formation, as well as DNA methylation after differentiation of the embryonic stem cells. Thus, natural antisense RNA may be a trigger for heterochromatin formation and DNA methylation in TSG silencing in tumorigenesis.
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PMID:Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. 1818 90


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