Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidermal growth factor receptor (EGFR) stimulates proliferative and survival signals. Activating mutations of EGFR are involved in the aetiology and maintenance of the malignant phenotype of lung tumours. We previously described the frequent association of these mutations with the decreased expression of the p14(ARF) tumour suppressor, another common feature of lung cancer. Based on these data, we postulated that p14(ARF) could protect cells against untimely or excessive mitotic signals induced by mutant EGFR. In this study, we demonstrate that p14(ARF) promotes apoptosis in lung tumour cells harbouring the EGFR L858R mutation through the accumulation of phosphorylated signal transducer and activator of transcription 3 (STAT3) on Tyr 705 residue, which leads to Bcl-2 downregulation. Using siRNA against PTP-RT, the phosphatase that specifically targets Tyr 705 residue, we show that accumulation of pSTAT3-Tyr705 promotes EGFR L858R mutant cell death, thereby confirming the existence of a STAT3-dependent pro-apoptotic pathway in these cells. Finally, we show that the expression of the EGFR L858R mutant represses p14(ARF) expression and inhibits STAT3/Bcl-2 signalling. These results identify a novel link between the p14(ARF) and EGFR pathways and suggest that EGFR L858R counteracts the pro-apoptotic function of p14(ARF) by downregulating its expression to promote carcinogenesis.
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PMID:p14(ARF) inhibits the growth of lung adenocarcinoma cells harbouring an EGFR L858R mutation by activating a STAT3-dependent pro-apoptotic signalling pathway. 2245 Jul 44

Exposure to asbestos is a risk for malignant mesothelioma (MM) in humans. Among the commercially used types of asbestos (chrysotile, crocidolite, and amosite), the carcinogenicity of chrysotile is not fully appreciated. Here, we show that all three asbestos types similarly induced MM in the rat peritoneal cavity and that chrysotile caused the earliest mesothelioma development with a high fraction of sarcomatoid histology. The pathogenesis of chrysotile-induced mesothelial carcinogenesis was closely associated with iron overload: repeated administration of an iron chelator, nitrilotriacetic acid, which promotes the Fenton reaction, significantly reduced the period required for carcinogenesis; massive iron deposition was found in the peritoneal organs with high serum ferritin; and homozygous deletion of the CDKN2A/2B/ARF tumour suppressor genes, the most frequent genomic alteration in human MM and in iron-induced rodent carcinogenesis, was observed in 92.6% of the cases studied with array-based comparative genomic hybridization. The induced rat MM cells revealed high expression of mesoderm-specific transcription factors, Dlx5 and Hand1, and showed an iron regulatory profile of active iron uptake and utilization. These data indicate that chrysotile is a strong carcinogen when exposed to mesothelia, acting through the induction of local iron overload. Therefore, an intervention to remove local excess iron might be a strategy to prevent MM after asbestos exposure.
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PMID:Iron overload signature in chrysotile-induced malignant mesothelioma. 2286 72

The epigenetic modifications have been reported to be key factors in breast carcinogenesis. In the current study, it has been tried to determine the methylation status of two tumour suppressor genes p14/ARF and p16/INK4a in 150 breast cancer patients as well as 150 controls by using MSP-PCR. There was, highly significant difference in methylation of p14/ARF and p16/INK4a (P=0.000) between patients and controls. Methylation of both the genes together significantly increased the risk of breast cancer by 12.31 folds. The present study concludes that hypermethylation of p14/ARF and p16/INK4a promoters demonstrate significant association with the risk of breast cancer, hence indicating these as important tumour suppressor genes involved in the pathogenesis of breast cancer in North Indian population (i.e. Punjab, Haryana, Uttar Pradesh, Himachal Pradesh as well as Union Territory of Chandigarh).
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PMID:Promoter hypermethylation of tumour suppressor genes (p14/ARF and p16/INK4a): case-control study in North Indian population. 2371 79

It has recently been shown that there are highly significant associations for common single nucleotide polymorphisms (SNPs) near the CDKN2B-AS1 gene region at the 9p21 locus with primary open angle glaucoma (POAG), a leading cause of irreversible blindness. This gene region houses the CDKN2B/p15(INK4B) , CDKN2A/p16(INK4A) and p14ARF (rat equivalent, p19(ARF) ) tumour suppressor genes and is adjacent to the S-methyl-5'-thioadenosine phosphorylase (MTAP) gene. In order to understand the ocular function of these genes and, therefore, how they may be involved in the pathogenesis of POAG, we studied the distribution patterns of each of their products within human and rat ocular tissues. MTAP mRNA was detected in the rat retina and optic nerve and its protein product was localised to the corneal epithelium, trabecular meshwork and retinal glial cells in both human and rat eyes. There was a very low level of p16(INK4A) mRNA present within the rat retina and slightly more in the optic nerve, although no protein product could be detected in either rat or human eyes with any of the antibodies tested. P19(ARF) mRNA was likewise only present at very low levels in rat retina and slightly higher levels in the optic nerve. However, no unambiguous evidence was found to indicate expression of specific P19(ARF)/p14(ARF) proteins in either rat or human eyes, respectively. In contrast, p15(INK4B) mRNA was detected in much higher amounts in both retina and optic nerve compared with the other genes under analysis. Moreover, p15(INK4B) protein was clearly localised to the retinal inner nuclear and ganglion cell layers and the corneal epithelium and trabecular meshwork in rat and human eyes. The presented data provide the basis for future studies that can explore the roles that these gene products may play in the pathogenesis of glaucoma and other models of optic nerve damage.
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PMID:Ocular expression and distribution of products of the POAG-associated chromosome 9p21 gene region. 2406 79

ARF is a tumour suppressor activated by oncogenic stress, which stabilizes p53. Although p53 is a key component of the response to DNA damage, a similar function for ARF has not been ascribed. Here we show that primary mouse and human cells lacking the tumour suppressor BRCA2 accumulate DNA damage, which triggers checkpoint signalling and ARF activation. Furthermore, senescence induced by Brca2 deletion in primary mouse and human cells is reversed by the loss of ARF, a phenotype recapitulated in cells lacking RAD51. Surprisingly, ARF is not necessary for p53 accumulation per se but for altering the spectrum of genes activated by this transcription factor. Specifically, ARF enables p53 transcription of Dusp4 and Dusp7, which encode a pair of phosphatases known to inactivate the MAP kinases ERK1/2. Our results ascribe a previously unanticipated function to the ARF tumour suppressor in genome integrity, controlled by replicative stress and ATM/ATR-dependent checkpoint responses.
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PMID:ARF triggers senescence in Brca2-deficient cells by altering the spectrum of p53 transcriptional targets. 2416 89

The ARF tumour suppressor protein, the gene of which is frequently mutated in many human cancers, plays an important role in the cellular stress response by orchestrating up-regulation of p53 protein and consequently promoting cell-cycle delay. Although p53 protein function has been clearly linked to the cellular DNA damage response, the role of ARF protein in this process is unclear. Here, we report that arf gene transcription is induced by DNA strand breaks (SBs) and that ARF protein accumulates in response to persistent DNA damage. We discovered that poly(ADP-ribose) synthesis catalysed by PARP1 at the sites of unrepaired SBs activates ARF transcription through a protein signalling cascade, including the NAD(+)-dependent deacetylase SIRT1 and the transcription factor E2F1. Our data suggest that poly(ADP-ribose) synthesis at the sites of SBs initiates DNA damage signal transduction by reducing the cellular concentration of NAD(+), thus down-regulating SIRT1 activity and consequently activating E2F1-dependent ARF transcription. Our findings suggest a vital role for ARF in DNA damage signalling, and furthermore explain the critical requirement for ARF inactivation in cancer cells, which are frequently deficient in DNA repair and accumulate DNA damage.
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PMID:ARF induction in response to DNA strand breaks is regulated by PARP1. 2429 53

Cullin4A (Cul4A) is a scaffold protein that assembles cullin-RING ubiquitin ligase (E3) complexes and regulates many cellular events, including cell survival, development, growth and cell cycle control. Our previous study suggested that Cul4A is oncogenic in vitro, but its oncogenic role in vivo has not been studied. Here, we used a Cul4A transgenic mouse model to study the potential oncogenic role of Cul4A in lung tumour development. After Cul4A over-expression was induced in the lungs for 32 weeks, atypical epithelial cells were observed. After 40 weeks, lung tumours were visible and were characterized as grade I or II adenocarcinomas. Immunohistochemistry (IHC) revealed decreased levels of Cul4A-associated proteins p21(CIP1) and tumour suppressor p19(ARF) in the lung tumours, suggesting that Cul4A regulated their expression in these tumours. Increased levels of p27(KIP1) and p16(INK4a) were also detected in these tumours. Moreover, the protein level of DNA replication licensing factor CDT1 was decreased. Genomic instability in the lung tumours was further analysed by the results from pericentrin protein expression and array comparative genomic hybridization analysis. Furthermore, knocking down Cul4A expression in lung cancer H2170 cells increased their sensitivity to the chemotherapy drug cisplatin in vitro, suggesting that Cul4A over-expression is associated with cisplatin resistance in the cancer cells. Our findings indicate that Cul4A is oncogenic in vivo, and this Cul4A mouse model is a tool in understanding the mechanisms of Cul4A in human cancers and for testing experimental therapies targeting Cul4A.
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PMID:Lung tumourigenesis in a conditional Cul4A transgenic mouse model. 2464 14

The ARF/INK4A (Cdkn2a) locus includes the linked tumour suppressor genes p16INK4a and p14ARF (p19ARF in mice) that trigger the antiproliferative activities of both RB and p53. With beta cell self-replication being the primary source for new beta cell generation in adult animals, the network by which beta cell replication could be increased to enhance beta cell mass and function is one of the approaches in diabetes research. In this review, we show a general view of the regulation points at transcriptional and posttranslational levels of Cdkn2a locus. We describe the molecular pathways and functions of Cdkn2a in beta cell cycle regulation. Given that aging reveals increased p16Ink4a levels in the pancreas that inhibit the proliferation of beta cells and decrease their ability to respond to injury, we show the state of the art about the role of this locus in beta cell senescence and diabetes development. Additionally, we focus on two approaches in beta cell regeneration strategies that rely on Cdkn2a locus negative regulation: long noncoding RNAs and betatrophin.
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PMID:Role of Ink4a/Arf locus in beta cell mass expansion under physiological and pathological conditions. 2467 5

The TP53 tumour suppressor is activated in response to distinct stimuli, including an ARF-dependent response to oncogene stress and an ATM/ATR-dependent response to DNA damage. In human T-cell acute lymphoblastic leukaemia (T-ALL), TP53-dependent tumour suppression is typically disabled via biallelic ARF deletions. In murine models, loss of Arf (Cdkn2a) or Tp53 markedly accelerates the onset of Myc-induced lymphoblastic malignancies. In zebrafish, no ARF ortholog has been identified, but the sequence of ARF is very poorly conserved evolutionarily, making it difficult to exclude the presence of a zebrafish ARF ortholog without functional studies. Here we show that tp53 mutations have no significant influence on the onset of myc-induced T-ALL in zebrafish, consistent with the lack of additional effects of Tp53 loss on lymphomagenesis in Arf-deficient mice. By contrast, irradiation leads to complete T-ALL regression in tp53 wild-type but not homozygous mutant zebrafish, indicating that the tp53-dependent DNA damage response is intact. We conclude that tp53 inactivation has no impact on the onset of myc-induced T-ALL in the zebrafish, consistent with the lack of a functional ARF ortholog linking myc-induced oncogene stress to tp53-dependent tumour suppression. Thus, the zebrafish model is well suited to the study of ARF-independent pathways in T-ALL pathobiology.
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PMID:Loss of function tp53 mutations do not accelerate the onset of myc-induced T-cell acute lymphoblastic leukaemia in the zebrafish. 2469 81

The JmjC domain-containing protein JMJD3/KDM6B catalyses the demethylation of H3K27me3 and H3K27me2. JMJD3 appears to be highly regulated at the transcriptional level and is upregulated in response to diverse stimuli such as differentiation inducers and stress signals. Accordingly, JMJD3 has been linked to the regulation of different biological processes such as differentiation of embryonic stem cells, inflammatory responses in macrophages, and induction of cellular senescence via regulation of the INK4A-ARF locus. Here we show here that JMJD3 interacts with the tumour suppressor protein p53. We find that the interaction is dependent on the p53 tetramerization domain. Following DNA damage, JMJD3 is transcriptionally upregulated and by performing genome-wide mapping of JMJD3, we demonstrate that it binds genes involved in basic cellular processes, as well as genes regulating cell cycle, response to stress and apoptosis. Moreover, we find that JMJD3 binding sites show significant overlap with p53 bound promoters and enhancer elements. The binding of JMJD3 to p53 target sites is increased in response to DNA damage, and we demonstrate that the recruitment of JMJD3 to these sites is dependent on p53 expression. Therefore, we propose a model in which JMJD3 is recruited to p53 responsive elements via its interaction with p53 and speculate that JMJD3 could act as a fail-safe mechanism to remove low levels of H3K27me3 and H3K27me2 to allow for efficient acetylation of H3K27.
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PMID:The histone lysine demethylase JMJD3/KDM6B is recruited to p53 bound promoters and enhancer elements in a p53 dependent manner. 2479 17


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