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)

The aim of this study was to identify genomic aberrations in endometrial cancer cells treated with the phyto-estrogenic compounds tectorigenin, irigenin and apigenin and to compare with those treated with beta-estradiol using array-based comparative genomic hybridisation (array CGH). The microarray contains 287 targets and includes telomeres, microdeletions, oncogenes and tumour suppressor genes and has increased mapping resolution compared to conventional CGH. An endometrial cancer cell line (Ishikawa) was cultured and treated with the phyto-estrogens. Treated cells were examined using the CGH microarray. Over 20 % of the array genes were aberrated in the cells treated with beta-estradiol, tectorigenin and irigenin compared to 3 % in those treated with the same concentration of apigenin. Protein kinase c zeta form, insulin, insulin receptor and protein-tyrosine phosphatase non-receptor-type 1 which are involved in insulin metabolism were aberrated by tectorigenin and irigenin. Apigenin may play a role in the treatment of endometrial cancer and in the treatment of postmenopausal women. Further studies in normal endometrium and primary endometrial cancer cells are needed to elucidate the role of the phyto-estrogens.
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PMID:Analysis of DNA in endometrial cancer cells treated with phyto-estrogenic compounds using comparative genomic hybridisation microarrays. 1593 82

Gangliogliomas and focal cortical dysplasias (FCDs) constitute glioneuronal lesions, which are frequently encountered in biopsy specimens of patients with pharmacoresistant focal epilepsy and relate to impaired differentiation and migration of neural precursors. However, their molecular pathogenesis and relationship are still largely enigmatic. Recent data suggest several components of the insulin-pathway, including TSC1 and TSC2 mutated in tuberous sclerosis complex (TSC), to be altered in gangliogliomas and FCD with Taylor type balloon cells (FCD(IIb)). The proteins tuberin (TSC2) and hamartin (TSC1) constitute a tumour suppressor mechanism involved in cell-cycle control. Hamartin and/or tuberin were reported to colocalize and/or interact with CDK1, cyclinB1 and cyclinA2 that are critically involved in cell-size and cell-growth control. Here, we have carried out mutational and expression analyses of CDK1, cyclinB1 and cyclinA2 in gangliogliomas and FCD(IIb). Mutational screening was performed by single-strand conformation polymorphism analysis in gangliogliomas (n = 20), FCD(IIb) (n = 35) and controls. CyclinB1 revealed a polymorphism (G to A, cDNA Position 966, GenBank: NM_031966) in exon 7 with similar frequencies in FCD(IIb), gangliogliomas and control specimens (FCD n = 9/35; gangliogliomas n = 5/20; control n = 20/100). We used real-time reverse transcription polymerase chain reaction to determine expression levels of CDK1, cyclinB1 and cyclinA2 in 10 FCD(IIb) and nine gangliogliomas compared with unaffected adjacent control tissue of the same patients. We observed significantly lower expression of CDK1 and cyclinA2 in FCD(IIb) vs. controls whereas no significant expression differences were present for CDK1, cyclinB1 and cyclinA2 in gangliogliomas. Our data strongly argue against mutational events of CDK1, cyclinB1 and cyclinA2 to play a role in gangliogliomas or FCD(IIb). However, a potential functional significance of lower expression for the cell-size and cell-cycle regulators CDK1 and cyclinA2 in FCD(IIb) composed of large dysplastic neurones and balloon cells needs to be further resolved.
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PMID:Mutational and expression analysis of CDK1, cyclinA2 and cyclinB1 in epilepsy-associated glioneuronal lesions. 1735 56

Nutrient overload induces constitutive S6K1 (S6 kinase 1) activation, which leads to insulin resistance by suppressing insulin-induced class I PI3K (phosphoinositide 3-kinase) signalling [Um, Frigerio, Watanabe, Picard, Joaquin, Sticker, Fumagalli, Allegrini, Kozma, Auwerx and Thomas (2004) Nature 431, 200-205]. This finding gave rise to the question of the mechanism by which nutrients, such as AAs (amino acids), enter the mTOR (mammalian target of rapamycin)/S6K1 signalling pathway. Counter to the prevailing view, our recent studies have shown that the AA input into the mTOR/S6K1 signalling pathway is not mediated by the tumour suppressor TSC1 (tuberous sclerosis complex 1)/TSC2 or its target, the proto-oncogene Rheb (Ras homologue enriched in brain). Instead, we found that the AA input was mediated by class 3 PI3K, or hVps34 (human vacuolar protein sorting 34). In brief, ectopic expression of hVps34 drives S6K1 activation, but only in the presence of AAs, and this effect is blocked by small interfering RNAs directed against hVps34. Moreover, stimulation of cells with AAs increases hVps34 activity, as indicated by the production of PI3P (phosphatidylinositol 3-phosphate). PI3P mediates the recruitment of proteins containing FYVE (Fab1p, YOTB, Vac1p and EEA1) or PX (Phox homology) domains to endosomal membranes, with PI3P-rich micro-domains acting as signalling platforms. Additional evidence indicating hVps34 as the mediator of AA input to S6K1 came from experiments in which S6K1 activation was attenuated by ectopic expression of a cDNA containing two FYVE domains, which bind to PI3P, preventing binding of proteins containing either FYVE or PX domains [Nobukuni, Joaquin, Roccio, Dann, Kim, Gulati, Byfield, Backer, Natt, Bos, Zwartkruis and Thomas (2005) Proc. Natl. Acad. Sci. U.S.A. 102, 14238-14243].
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PMID:Nutrient sensing in the mTOR/S6K1 signalling pathway. 1737 Dec 47

PTEN (phosphatase and tensin homologue deleted on chromosome 10) is well known as a tumour suppressor. In dephosphorylating the 3-position of the inositol ring of phosphoinositides such as PtdIns(3,4,5)P(3), PTEN's lipid phosphatase activity is an important counteracting mechanism in PI3K (phosphoinositide 3-kinase) signalling. This is essential for cell motility and migration due to the achievement of a PtdIns(3,4,5)P(3)/PtdIns(4,5)P(2) gradient that is also involved in metastasis. Furthermore, PTEN's tumour suppressor role is linked to the control of cell-cycle progression and cell proliferation by counteracting Akt (also called protein kinase B) signalling which is PtdIns(3,4,5)P(3)-dependent. Akt is upstream of several kinases involved in proliferation and apoptotic signalling which are often found to be deregulated or mutated in tumours. However, Akt is also the key enzyme in insulin signalling regulating glucose uptake and cell growth. Therefore PTEN has recently moved into the spotlight as a drug target in diabetes. This review summarizes studies undertaken on PTEN's role in glucose uptake, insulin resistance, diabetes and its controversial role in GLUT (glucose transporter)-mediated glucose uptake. Currently available techniques for inhibiting PTEN and the suitability of PTEN as a drug target will be discussed.
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PMID:Inhibiting PTEN. 1737 Dec 53

The insulin-like growth factor (IGF) is a complex system of peptide hormones (insulin-like growth factors of type 1 and 2, IGF-1 and IGF-2), cell surface receptors (insulin receptor, IR; insulin-like growth factor receptors of type 1 and 2, IGF-R1, IGF-R2) and circulating binding proteins (insulinlike growth factor binding proteins, IGF-BP 1-6). IGF-1 and -2 are mitogens that play a role in regulating cell proliferation, differentiation and apoptosis. Their effects are mediated through the IGF-R1 which initiates signaling cascades that result in regulation of a number of biological responses. IGF-R2, together with IGF-BPs is involved in binding, internalization and degradation of IGF-2. IGF proteins regulate cell proliferation in an interconnected action via autocrine, paracrine and endocrine regulatory mechanisms. Consequently, any perturbation in each level of the IGF signaling proteins has been shown to be implicated in development and progression of numerous cancer types. The most important single components in this processes are IGF ligands as well as IGF-R1 - when disturbed they act as oncogenes. It has been shown that: (i) high serum concentrations of IGF-1 and IGF-2 are associated with an increased risk of breast, prostate, colorectal and lung cancers; and (ii) IGF-R1 is commonly disturbed in many tumours (like gastric, lung, endometrial cancer) leading to a phenotype of anchorage-independent tumour growth. In contrast, IGF-R2 is considered to act as a tumour suppressor gene; it protects the cells from neoplastic impulses. Consistent with the IGFs autocrine/paracrine regulation of tumour growth, cancer treatment strategies interfering with IGF-R1 signaling have been developed, that may be useful in future diagnostic and therapeutic strategies.
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PMID:Biological & physiological aspects of action of insulin-like growth factor peptide family. 1759 37

When Chinese hamster ovary (CHO) cells were grown in suspension and deprived of serum, 40% of them became apoptotic after 72 hours, as determined by flow cytometry analysis of TUNEL-labelled cells. Cell viability, assessed by erythrocin B staining, decreased correspondingly. An increase in the total fraction of cells expressing interleukin converting enzyme (ICE; caspase 1), B-cell lymphoma 2 protein (Bcl-2,) and Bcl-2 associated x protein (Bax) was shown by antibody probing and subsequent flow cytometry. The p53 tumour suppressor gene product level remained low within the cell population. Insulin-like growth factor-1 (IGF-1) inhibited cell death in a concentration-dependent manner, and at 20 ng/ml, cell viability was maintained close to 100% and no apoptotic cells were detected. Also, insulin was shown to inhibit cell death - at 1.0 microg/ml, cell viability was 95%, whereas 10% of the cells stained for apoptosis. At the highest concentrations of IGF-1 and insulin, the expression of ICE, Bcl-2 and Bax was fully suppressed, whereas the p53 product level increased, despite still being detectable in a minority of cells. Under these conditions, IGF-1 may increase p53 expression to restrain abnormal cell proliferation. It is concluded that special attention should be paid to exposure and culture conditions that induce acquired susceptibility to a toxic insult, during the development and validation of cell-based assays.
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PMID:Insulin and IGF-1 mediated inhibition of apoptosis in CHO cells grown in suspension in a protein-free medium. 1765 Sep 54

Islet function is dependent on cells within the islet interacting with each other. E-cadherin (ECAD) mediates Ca(2+)-dependent homophilic cell adhesion between b-cells within islets and has been identified as a tumour suppressor. We generated clones of the MIN6 beta-cell line that stably over- (S) and under-express (alphaS) ECAD. Modified expression of ECAD was confirmed by quantitative RT-PCR, immunoblotting and immunocytochemistry. Preproinsulin mRNA, insulin content and basal rates of insulin secretion were higher in S cells compared to aS and control (V) cells. However, stimulated insulin secretory responses were unaffected by ECAD expression levels. ECAD expression did affect proliferation, with enhanced ECAD expression being associated with reduced proliferation and vice versa. Formation of islet-like structures was associated with a significant reduction in proliferation of V and S cells but not alphaS cells. These data suggest that ECAD expression levels do not modulate insulin secretory function but are consistent with a role for ECAD in the regulation of beta-cell proliferation.
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PMID:E-cadherin interactions regulate beta-cell proliferation in islet-like structures. 1776 88

Immune-independent diabetes often occurs via pancreatic beta cell dysfunction. However, the role of the tumour suppressor p53 that regulates cellular life and death in multiple tissues, in pancreatic cell death and diabetes has not been clarified. We have therefore utilized an established mouse model for diabetes in which the MHC class I antigen is overexpressed in pancreatic beta cells under the rat insulin promoter, to investigate the role of p53. We show that pancreatic beta cell death, as determined by TUNEL staining, is elevated in transgenic mice compared to wild-type mice. However, there was no increase in immuno-reactivity towards anti-p53 antibodies in the pancreas of transgenic mice over the course of diabetes formation and beta cell death, suggesting that p53 may not be involved in these processes. Interestingly, p53 expression was also not induced in pancreas upon gamma-irradiation, which resulted in a massive increase in the number of TUNEL-positive cells, suggesting that the p53 pathway may not be causally involved in pancreatic cell death. To further confirm these findings, we generated MHC class I transgenic mice lacking p53 expression. Absence of p53 did not result in any significant changes in pancreatic morphology or affect cell death levels. Importantly, p53 absence did not rescue the diabetic phenotype of the transgenic mice. The results therefore demonstrate that p53 may not be causally involved in pancreatic beta cell death, and suggests that the classical cell death pathway dependent on p53 may not be operating in pancreatic beta cells.
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PMID:The tumour-suppressor p53 is not required for pancreatic beta cell death during diabetes and upon irradiation. 1800 84

Recently, a large cluster of homeobox genes was discovered on the X chromosome that is expressed in reproductive tissues after birth. It is postulated that these reproductive homeobox genes on the X chromosome (Rhox) encode transcription factors that regulate gametogenesis. In support of this, male mice lacking the founding member of this gene cluster, Rhox5, are subfertile, exhibiting increased germ-cell apoptosis and a defect in sperm motility. To identify RHOX5 targets, microarray analyses were used to identify genes differently expressed in postnatal testes from Rhox5-null and control littermates. Highly overrepresented were genes that encode proteins involved in cellular metabolism. Several lines of evidence indicated that one of these, insulin II, is a direct target of RHOX5. Microarray analysis was also used to identify genes differentially expressed in response to physiological levels of Rhox5 in a Sertoli-cell line. Among the few genes identified, the netrin-1 receptor UNC5c, a proapoptotic molecule that is inhibited by RHOX5, was also regulated in vivo, and is thus a candidate to be downstream of RHOX5 in a prosurvival germ-cell pathway. To understand the means by which Rhox5 expression is restricted to Sertoli nurse cells in the testis, a variety of molecular approaches were used in both Sertoli-cell lines and mice. This analysis revealed that both positive and negative cis elements collaborate to confer Sertoli cell-specific gene expression. Acting on the positive cis elements are androgen receptor and GATA transcription factors. Collectively, the results of this study provide an initial glimpse into the regulatory networks that control spermatogenesis.
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PMID:Regulation and function of the Rhox5 homeobox gene. 1818 11

The PTEN tumour suppressor encodes a phosphatase, and its daf-18 orthologue in Caenorhabditis elegans negatively regulates the insulin/IGF-1 DAF-2 receptor pathway that influences lifespan in worms and other species. In order to identify new DAF-18 regulated pathways involved in aging, we initiated a candidate RNAi feeding screen for clones that lengthen lifespan. Here, we report that smg-1 inactivation increases average lifespan in a daf-18 dependent manner. Genetic analysis is consistent with SMG-1 acting at least in part in parallel to the canonical DAF-2 receptor pathway, but converging on the transcription factor DAF-16/FOXO. SMG-1 is a serine-threonine kinase which plays a conserved role in nonsense-mediated mRNA decay (NMD) in worms and mammals. In addition, human SMG-1 has also been implicated in the p53-mediated response to genotoxic stress. The effect of smg-1 inactivation on lifespan appears to be unrelated to its NMD function, but requires the p53 tumour suppressor orthologue cep-1. Furthermore, smg-1 inactivation confers a resistance to oxidative stress in a daf-18-, daf-16- and cep-1-dependent manner. We propose that the role of SMG-1 in lifespan regulation is at least partly dependent on its function in oxidative stress resistance. Taken together, our results unveil a novel role for SMG-1 in lifespan regulation.
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PMID:A novel role for the SMG-1 kinase in lifespan and oxidative stress resistance in Caenorhabditis elegans. 1883 29


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