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)

Tobacco smoking is the leading cause of lung cancer worldwide. Gene expression in surgically resected and microdissected samples of non-small-cell lung cancers (18 squamous cell carcinomas and nine adenocarcinomas), matched normal bronchial epithelium, and peripheral lung tissue from both smokers (n = 22) and non-smokers (n = 5) was studied using the Affymetrix U133A array. A subset of 15 differentially regulated genes was validated by real-time PCR or immunohistochemistry. Hierarchical cluster analysis clearly distinguished between benign and malignant tissue and between squamous cell carcinomas and adenocarcinomas. The bronchial epithelium and adenocarcinomas could be divided into the two subgroups of smokers and non-smokers. By comparison of the gene expression profiles in the bronchial epithelium of non-smokers, smokers, and matched cancer tissues, it was possible to identify a signature of 23 differentially expressed genes, which might reflect early cigarette smoke-induced and cancer-relevant molecular lesions in the central bronchial epithelium of smokers. Ten of these genes are involved in xenobiotic metabolism and redox stress (eg AKR1B10, AKR1C1, and MT1K). One gene is a tumour suppressor gene (HLF); two genes act as oncogenes (FGFR3 and LMO3); two genes are involved in matrix degradation (MMP12 and PTHLH); three genes are related to cell differentiation (SPRR1B, RTN1, and MUC7); and five genes have not been well characterized to date. By comparison of the tobacco-exposed peripheral alveolar lung tissue of smokers with non-smokers and with adenocarcinomas from smokers, it was possible to identify a signature of 27 other differentially expressed genes. These genes are involved in the metabolism of xenobiotics (eg GPX2 and FMO3) and may represent cigarette smoke-induced, cancer-related molecular targets that may be utilized to identify smokers with increased risk for lung cancer.
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PMID:Smoking and cancer-related gene expression in bronchial epithelium and non-small-cell lung cancers. 1691 69

Tumorigenesis is a multi-step process that requires activation of oncogenes and inactivation of tumour suppressor genes. Mouse models of human cancers have recently demonstrated that continuous expression of a dominantly acting oncogene (for example, Hras, Kras and Myc) is often required for tumour maintenance; this phenotype is referred to as oncogene addiction. This concept has received clinical validation by the development of active anticancer drugs that specifically inhibit the function of oncoproteins such as BCR-ABL, c-KIT and EGFR. Identifying additional gene mutations that are required for tumour maintenance may therefore yield clinically useful targets for new cancer therapies. Although loss of p53 function is a common feature of human cancers, it is not known whether sustained inactivation of this or other tumour suppressor pathways is required for tumour maintenance. To explore this issue, we developed a Cre-loxP-based strategy to temporally control tumour suppressor gene expression in vivo. Here we show that restoring endogenous p53 expression leads to regression of autochthonous lymphomas and sarcomas in mice without affecting normal tissues. The mechanism responsible for tumour regression is dependent on the tumour type, with the main consequence of p53 restoration being apoptosis in lymphomas and suppression of cell growth with features of cellular senescence in sarcomas. These results support efforts to treat human cancers by way of pharmacological reactivation of p53.
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PMID:Restoration of p53 function leads to tumour regression in vivo. 1725 31

The aim of the present study was to evaluate the association between different types of hormone replacement therapy (HRT) and risk of specific breast cancer subgroups. A population-based prospective cohort study including 12,583 peri- or postmenopausal women were followed using record-linkage with national cancer registries. During an average follow-up of 4.5 years, 332 cases of invasive breast cancer were diagnosed. Tumour samples were available from 283 cases. These tumours were re-evaluated according to histological type, grade, and mitotic index. Evaluation of tumours included estrogen and progesterone receptor status (ERalpha, ERbeta and PgR), as well as expression of Ki67, HER2, cyclin D1 and p27. The incidence of breast cancer in current users of combined HRT (CHRT) was significantly higher than in non-users. The difference corresponded to an adjusted relative risk (95% confidence interval) of 3.01 (2.35-3.84) as obtained using a Cox's proportional hazards analysis. CHRT was associated with lobular tumours (3.48:1.99-6.10), grade 1 tumours (4.46:2.79-7.13) and tumours with a low mitotic index (4.35:2.99-6.34). CHRT was not related to any specific subgroup in terms of ERalpha-, ERbeta- or PgR-expression. CHRT was associated with low proliferating tumours, defined by the Ki67 index (3.58:2.60-4.93), HER2 amplified tumours (4.40:1.93-10.06), low expression of the oncogene cyclin D1 (3.14:2.32-4.23) and high expression of the tumour suppressor gene p27 (3.47:2.40-5.01). Use of estrogen-alone HRT (ERT) was not associated with any statistically significant risk of breast cancer. We conclude that the use of CHRT is associated with an increased incidence of breast tumours with comparatively favourable prognostic factors.
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PMID:Breast tumours following combined hormone replacement therapy express favourable prognostic factors. 1727 89

The cyclin-dependent kinase inhibitor p21WAF1/CIP1, a critical regulator of the cell cycle, is mainly regulated by p53 tumour suppressor at the transcriptional level. Restoration of p21WAF1/Cip1 expression in p53-deficient malignant cells suppress tumour growth. Cyclosporine A (CsA) affects proliferation and survival of cultured malignant glioma cells and impairs growth of experimental gliomas. CsA induced p21WAF1/Cip1 expression de novo in human glioblastoma cells with p53 deficiency. We demonstrate that transcriptional activation of p21WAF1/Cip1 expression correlated with induction of ERK1/2 and c-Jun phosphorylation in CsA-treated glioblastoma cells. Pre-treatment with ERK pathway inhibitors or overexpression of dominant-negative mutants MKK1, ERK2 and c-Jun reduced activation of the p21WAF1/Cip1 promoter. Overexpression of tethered AP-1 dimers containing c-Jun was sufficient to activate the truncated -200 bp p21WAF1/Cip1 promoter, which does not contain p53 binding sites. Chromatin immunoprecipitation revealed that P-c-Jun is bound to the proximal part of p21WAF1/Cip1 promoter in CsA-treated glioblastoma cells. It suggests that CsA activates p53-independent, transcriptional activation p21WAF1/Cip1 expression, mediated by ERK/c-Jun/AP-1 signaling pathway.
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PMID:Alternative pathway of transcriptional induction of p21WAF1/Cip1 by cyclosporine A in p53-deficient human glioblastoma cells. 1732 21

Multiple endocrine neoplasia (MEN) are major predisposition syndromes to endocrine tumours and are characterised by an autosomal dominant disorder and full penetrance. MEN-1 is a major form of hyperparathyroidism associated with a high prevalence of endocrine tumours of the pancreas, pituitary gland, adrenal cortex and the lymphoid and bronchial endocrine tissues. MEN-2 is the familial syndrome of medullary thyroid carcinoma, associated with pheochromocytoma and hyperparathyroidism. Apart from the clinical expression of their allelic variants, both syndromes are different in their physiopathogenesis, in that MEN-2 is related to the constitutional activation of the proto-oncogene RET that encodes a putative tyrosine kinase receptor, while MEN-1 is a tumour suppressor gene model, related to mutations in the menin adapter-protein of multiple intracellular functions. The study of other rarer forms of predisposition to endocrine tumours, and especially to hyperparathyroidism, has uncovered new genes such as HRPT2, which show that multiple physiological routes, including the close regulation of transcription and genetic stability, may lead to the same clinical outcome. These hereditary models of endocrine cancer contribute as much to further physiopathogenic knowledge as to the therapeutic recommendations for managing these syndromes.
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PMID:[Pathogenic patterns of genetic predisposition to endocrine tumors]. 1737 13

Three human leucine-rich repeats and immunoglobulin-like domains (LRIG) genes and proteins, named LRIG1-3, has been previously characterized and it was proposed that they may act as suppressors of tumor growth. The LRIG1 protein can inhibit the growth of tumors of glial cells and the down-regulation of the LRIG1 gene may be involved in the development and progression of the tumor. Real-time reverse transcription-polymerase chain reaction (RT-PCR) is a recently developed technique for quantitative assessment of specific RNA levels. In the current study, it was demonstrated that LRIG1-3 and EGFR mRNA was detected in human pituitary adenoma cell lines and a normal pituitary sample, with differences in the expression levels. Compared to the normal pituitary samples, the expression of LRIG1-3 in HP75 cell line was lower, but the expression of EGFR in HP75 cell line was higher. The results are consistent with LRIG1-3 being tumour suppressor genes, and LRIG genes decreasing the expression of EGFR. The ratio of EGFR/LRIG1 was increased at least 13-fold in HP75 cells compared with the normal pituitary cells, which was also the case for the ratio of EGFR/LRIG2 (14-fold increase in HP75) and EGFR/LRIG3 (11-fold increase in HP75). Further studies were needed to elucidate the explicit role of LRIG genes as negative regulators of oncogenesis in human pituitary adenoma.
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PMID:Down-regulation of leucine-rich repeats and immunoglobulin-like domain proteins (LRIG1-3) in HP75 pituitary adenoma cell line. 1739 20

The ataxia-telangiectasia-mutated (ATM) kinase is a key transducer of DNA damage signals within the genome maintenance machinery and a tumour suppressor whose germline mutations predispose to familial breast cancer. ATM signalling is constitutively activated in early stages of diverse types of human malignancies and cell culture models in response to oncogene-induced DNA damage providing a barrier against tumour progression. As BRCA1 and BRCA2 are also components of the genome maintenance network and their mutations predispose to breast cancer, we have examined the ATM expression in human breast carcinomas of BRCA1/2 mutation carriers, sporadic cases and familial non-BRCA1/2 patients. Our results show that ATM protein expression is aberrantly reduced more frequently among BRCA1 (33%; P=0.0003) and BRCA2 (30%; P=0.0009) tumours than in non-BRCA1/2 tumours (10.7%). Furthermore, the non-BRCA1/2 tumours with reduced ATM expression were more often estrogen receptor (ER) negative (P=0.0002), progesterone receptor (PR) negative (P=0.004) and were of higher grade (P=0.0004). In our series of 1013 non-BRCA1/2 cases, ATM was more commonly deficient (20%; P=0.0006) and p53 was overabundant (47%; P<0.0000000001) among the difficult-to-treat ER/PR/ERBB2-triple-negative subset of tumours compared with cases that expressed at least one of these receptors (10 and 16% of aberrant ATM and p53, respectively). We propose a model of 'conditional haploinsufficiency' for BRCA1/2 under conditions of enhanced DNA damage in precancerous lesions resulting in more robust activation and hence increased selection for inactivation or loss of ATM in tumours of BRCA1/2 mutation carriers, with implications for genomic instability and curability of diverse subsets of human breast cancer.
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PMID:The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer. 1798 90

Oral squamous cell carcinoma (OSCC) is a common cancer characterised by low survival rate and poor prognosis. The multistep process of oral carcinogenesis is affected by multiple genetic events such as alterations of oncogenes and tumour suppressor genes. The use of appropriate experimental animal models that accurately represent the cellular and molecular changes which are associated with the initiation and progression of human oral cancer is of crucial importance. The Syrian golden hamster cheek pouch oral carcinogenesis model is the best known animal system that closely correlates events involved in the development of premalignant and malignant human oral cancers. Therefore, we established an experimental system of chemically induced oral carcinogenesis in hamsters, in order to study different stages of tumour formation: normal mucosa, hyperkeratosis, hyperplasia, dysplasia, early invasion, well differentiated OSCC and moderately differentiated OSCC. We investigated the expression of oncogenes EGFR, erbB2, erbB3, FGFR-2, FGFR-3, c-myc, N-ras, ets-1, H-ras, c-fos and c-jun, apoptosis markers Bax and Bcl-2, tumour suppressor genes p53 and p16, and cell proliferation marker Ki-67 in the sequential stages of hamster oral oncogenesis. Here, we describe the findings of the experimental model in regard to the involvement of signal transduction pathways in every stage of cancer development. Increased apoptosis and cell proliferation were observed in early stages of oral oncogenesis. Furthermore, the increased expression of transmembrane receptors (EGFR, erbB2, FGFR-2 and FGFR-3) as well as the increased expression of nuclear transcriptional factors in early stages of oral cancer indicates that these molecules may be used as early prognostic factors for the progression of OSCC. Since the expression of both H-ras and N-ras do not seem to affect signal transduction during oral oncogenesis, it can be assumed that a different signalling pathway, such as the PI3K and/or PLCgamma pathway, may be implicated in the pathogenesis of OSCC.
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PMID:The hamster model of sequential oral oncogenesis. 1806 31

The human lgl gene, Hugl-2 (llgl2, Lgl2), codes for a cytoskeletal protein involved in regulating cell polarity. Here, we report the identification and functional characterization of the promoter region ( approximately 1.2kb) of the Hugl-2 gene. Luciferase expression assays show a high basal Hugl-2 promoter activity in different cell lines and primary human hepatocytes. Truncations of the promoter identified a GC-rich region important for this activity. Alignment of human and mouse genomic sequences demonstrate that this is an evolutionary conserved region fcontaining putative binding sites for several transcription factors including Elk-1 and Sp-1. Mithramycin A reduces Hugl-2 expression indicating Sp-1 transcription factors activate Hugl-2. Treatment of primary hepatocytes with epidermal growth factor (EGF) suppresses Hugl-2, suggesting regulation by the EGF-signaling pathway. Downregulation of Hugl-2 by EGF may contribute to loss of cell polarity and tumour progression, therefore supporting a tumour suppressor role for Hugl-2.
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PMID:Cloning and characterization of the promoter of Hugl-2, the human homologue of Drosophila lethal giant larvae (lgl) polarity gene. 1815 65

1. Recent clinical and fundamental research studies have revolutionized our understanding of the genetics of phaeochromocytoma (PH) and functional paraganglioma (FPGL). It was widely thought that only 10% of PH patients had familial disease and that the malignant phenotype of PH could not be diagnosed before occurrence of the first metastasis. 2. Human genetic studies have now shown that 25-30% of patients have hereditary PH due to a germline mutation in the SDHB, SDHD, VHL, RET or NF1 gene and that the identification of a germline SDHB mutation is associated with a high risk of malignancy and a poor prognosis in PH/PGL patients. 3. Fundamental research studies have shown that SDH genes are tumour suppressor genes and that succinate dehydrogenase inactivation induces abnormal stimulation of the hypoxia-angiogenesis pathway. 4. Finally various fundamental research studies, conducted through the Cortico and Medullo-surrenale: les Tumeurs Endocrines (COMETE) network in France and by other groups worldwide, have produced new recommendations for genetic counselling and testing and for the management of PH patients. They have also improved our understanding of the molecular mechanisms involved in PH tumorigenesis.
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PMID:Recent advances in the genetics of phaeochromocytoma and functional paraganglioma. 1830 24


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