Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inactivation of the NF2 tumor suppressor gene has been observed in certain benign and malignant tumors. Recent studies have demonstrated that merlin, the product of the NF2 gene, is regulated by Rac/PAK signaling. However, the mechanism by which merlin acts as a tumor suppressor has remained obscure. In this report, we show that adenovirus-mediated expression of merlin in NF2-deficient tumor cells inhibits cell proliferation and arrests cells at G1 phase, concomitant with decreased expression of cyclin D1, inhibition of CDK4 activity, and dephosphorylation of pRB. The effect of merlin on cell cycle progression was partially overridden by ectopic expression of cyclin D1. RNA interference experiments showed that silencing of the endogenous NF2 gene results in upregulation of cyclin D1 and S-phase entry. Furthermore, PAK1-stimulated cyclin D1 promoter activity was repressed by cotransfection of NF2, and PAK activity was inhibited by expression of merlin. Interestingly, the S518A mutant form of merlin, which is refractory to phosphorylation by PAK, was more efficient than the wild-type protein in inhibiting cell cycle progression and in repressing cyclin D1 promoter activity. Collectively, our data indicate that merlin exerts its antiproliferative effect, at least in part, via repression of PAK-induced cyclin D1 expression, suggesting a unifying mechanism by which merlin inactivation might contribute to the overgrowth seen in both noninvasive and malignant tumors.
Mol Cell Biol 2005 Mar
PMID:The NF2 tumor suppressor gene product, merlin, inhibits cell proliferation and cell cycle progression by repressing cyclin D1 expression. 1574 31

Tumor-specific alterations at the RB1 gene locus in 30 human vestibular schwannomas including 10 NF2 and 20 sporadic cases were analysed. Southern blot analysis of DNA from these samples revealed loss of heterozygosity (LOH) at the RB1 locus in 6 of 24 informative cases (25%) compared to normal blood DNAs from the same patients. Northern blot analysis showed normal size RB1 mRNA in all the tumor samples. However, there was a 2-5-fold increase in the level of expression of the RB1 gene in all the tumor samples compared to the WI38 cell line which was used as control. Western blot analysis of the RB1 protein, pRb showed a 2.5-5-fold increase in the level of total pRb as compared to normal WI38 cell line. Sixty five to seventy five percent of the total pRb were in phosphorylated form in most tumors. The LOH at the RB1 gene locus suggests genetic instability in these patients. Further, increased levels of RB1 mRNA, total pRb and the phosphorylated form of pRb suggests that RB1 gene in these tumors may have anti-apoptotic function. These results suggest that the RB1 gene has a major role in the development of human vestibular schwannomas.
Mol Cell Biochem 2005 Mar
PMID:Altered structure and expression of RB1 gene and increased phosphorylation of pRb in human vestibular schwannomas. 1588 62

The DAL-1/41B gene (differentially expressed in adenocarcinoma of the lung), located in the chromosome 18p11.3 region, belongs to the protein family 4.1 (membrane-associated proteins), which includes the product of the NF2 gene (merlin), and the proteins, ezrin, radixin, and moesin. DAL-1/4.1B is normally expressed at high levels in the brain, with lower levels in the kidney, intestine, and testis. DAL-1/4.1B is known to suppress growth in meningiomas and can be lost in about 60% of sporadic meningiomas as an early event in tumorigenesis; it is a critical growth regulator in the pathogenesis of neoplastic transformation. The similarity between the DAL-1/4.1B protein and merlin, with their high levels of expression in the brain and their recurrent loss in meningiomas, and the lack of previous DAL-1/4.1B mutational analysis reports initiated this mutational study of DAL-1/4.1B in a series of 83 meningiomas. We found the following sequence variations; Ala555Thr (G1663A in exon 13) and Thr950Lys (C2849A in exon 19) in two cases each, and one case with a 5pb deletion (del taaaa) in intron 18. A polymorphism in exon 14 (C2112T/Thr704Thr, also known as C2166T) was also identified; the tumoral allelic constitutions were heterozygous C/T in 15, homo- or hemizygous C in 67 and hemizygous T in one tumour. The low mutational frequency in our study discounts sequence variations in DAL-1/4.1B as the main mechanism underlying participation of this gene in the neoplastic transformation of meningiomas, and suggests that other inactivating mechanisms, such as epigenetic changes, may participate in DAL1/4.1B silencing.
Int J Mol Med 2005 Oct
PMID:Mutational analysis of the DAL-1/4.1B tumour-suppressor gene locus in meningiomas. 1614 20

The effect of methionine deprivation (methionine stress) on the proliferation, survival, resistance to chemotherapy, and regulation of gene and protein expression in pancreatic tumor lines is examined. Methionine stress prevents successful mitosis and promotes cell cycle arrest and accumulation of cells with multiple micronuclei with decondensed chromatin. Inhibition of mitosis correlates with CDK1 down-regulation and/or inhibition of its function by Tyr(15) phosphorylation or Thr(161) dephosphorylation. Inhibition of cell cycle progression correlates with loss of hyperphosphorylated Rb and up-regulation of p21 via p53 and/or transforming growth factor-beta (TGF-beta) activation depending on p53 status. Although methionine stress-induced toxicity is not solely dependent on p53, the gain in p21 and loss in CDK1 transcription are more enhanced in wild-type p53 tumors. Up-regulation of SMAD7, a TGF-beta signaling inhibitor, suggests that SMAD7 does not restrict the TGF-beta-mediated induction of p21, although it may prevent up-regulation of p27. cDNA oligoarray analysis indicated a pleiotropic response to methionine stress. Cell cycle and mitotic arrest is in agreement with up-regulation of NF2, ETS2, CLU, GADD45alpha, GADD45beta, and GADD45gamma and down-regulation of AURKB, TOP2A, CCNA, CCNB, PRC1, BUB1, NuSAP, IFI16, and BRCA1. Down-regulation of AREG, AGTR1, M-CSF, and EGF, IGF, and VEGF receptors and up-regulation of GNA11 and IGFBP4 signify loss of growth factor support. PIN1, FEN1, and cABL up-regulation and LMNB1, AREG, RhoB, CCNG, TYMS, F3, and MGMT down-regulation suggest that methionine stress sensitizes the tumor cells to DNA-alkylating drugs, 5-fluorouracil, and radiation. Increased sensitivity of pancreatic tumor cell lines to temozolomide is shown under methionine stress conditions and is attributed in part to diminished O(6)-methylguanine-DNA methyltransferase and possibly to inhibition of the cell cycle progression.
Mol Cancer Ther 2005 Sep
PMID:Modulation of cell cycle and gene expression in pancreatic tumor cell lines by methionine deprivation (methionine stress): implications to the therapy of pancreatic adenocarcinoma. 1617 25

Tumor-specific alterations at the p53 gene locus in 30 human vestibular schwannomas (VS) comprising 10 confirmed NF2 cases and 20 sporadic cases were analyzed. We found loss of heterozygosity (LOH) at the first intron of the p53 gene locus in 54% of the informative cases. This is the first report showing LOH at the p53 gene locus in a significant number of human VS and both sporadic and NF2 cases show the LOH event. Increased levels of normal size p53 mRNA and p53 protein were found in all the tumors analyzed. Thus p53 appears to be deregulated in all the tumors suggesting that p53 alterations may be associated with tumor progression in VS. There was a negative significant correlation of patients' age and percentage of Ser 392 phosphorylated p53 protein. The tumor samples obtained from younger patients of 35 yr and below showed higher percentage of Ser 392 phosphorylated p53 protein compared to the tumors of older patients. The increased percentage of Ser 392 phosphorylated p53 protein indicates that it could be involved in the acceleration of tumor growth in the younger patients. Our results suggest that age dependent phosphorylation of p53 protein and deregulation of p53 gene has a role in the development of human vestibular schwannomas.
Mol Carcinog 2006 Jan
PMID:Age dependent phosphorylation and deregulation of p53 in human vestibular schwannomas. 1629 9

A new reliable and cost-efficient solid phase extraction-based clean-up method for the determination of 12 type A and B trichothecenes [deoxynivalenol (DON), nivalenol, 3-acetyldeoxynivalenol, 15-acetyldeoxynivalenol, fusarenon-X, T-2 toxin, HT-2 toxin, neosolaniol, monoacetoxy-scirpenol, diacetoxyscirpenol, T-2 triol and T-2 tetraol] in cereals and cereal-based food is presented. Furthermore, the suitability for the simultaneous determination of zearalenone is examined. Toxins were extracted from cereal samples using ACN/water (80/20, v/v), purified by means of a new Bond Elut Mycotoxin column and analyzed via liquid chromatography-electrospray ionization tandem mass spectrometry. Limits of detection were calculated for the matrix wheat and ranged from 0.3 to 5 ng/g, depending on the toxin. Average recovery rates for the tested compounds in seven cereal-based matrices have been determined ranging from 65 to 104%. The relative standard deviations of the complete method ranged from 2.67 (DON, wheat) to 20.0% (T-2 toxin, oats).
Mol Nutr Food Res 2006 Mar
PMID:A new solid phase extraction clean-up method for the determination of 12 type A and B trichothecenes in cereals and cereal-based food by LC-MS/MS. 1652 Nov 59

The NF2 tumor suppressor gene, located in chromosome 22q12, is involved in the development of sporadic meningiomas of the nervous system. In order to evaluate the role of the NF2 gene in sporadic meningiomas, we analyzed the entire coding regions of the NF2 gene in a group of 42 sporadic meningiomas: 17 meningothelial, 11 transitional, 11 fibrous, one secretory, one atypical, and one malignant subtype, using denaturing high-performance liquid chromatography (DHPLC) and sequence analysis. Twenty-one mutations were identified in 20 patients with an overall mutation detection rate of 47.6%. The mutations included nine deletions (exons 1, 2, 5, 10, and 12), resulting in a frameshift, four non-sense mutations (exons 1, 2, and 7), four splice errors (exons 4, 5, 7, and 12), two missense mutations (exon 5) and two silent mutations (exon 11). Among these, 14 novel mutations were also identified in the present study. All mutations were noted in the first 12 exons, the region of homology with the ezrin-moesin-radixin protein. Furthermore, an association between NF2 mutations and histologic subtypes were observed; NF2 mutations were more frequent in fibrous meningiomas (8/11, 73%) and transitional meningiomas (6/11, 55%), than in meningothelial variant (5/17, 29%). These results provide evidence that mutations in the NF2 gene play an important role in the development of sporadic meningiomas as well as indicating a different tumorigenesis of these meningioma variants.
Int J Mol Med 2006 Jul
PMID:Mutational analysis of the NF2 gene in sporadic meningiomas by denaturing high-performance liquid chromatography. 1678 52

Raman spectra of pure liquid dimethylsulfoxide (DMSO) and of binary mixtures of formamide (FA) and DMSO in different compositions were obtained. The vibrations involving the SO functional group in the band envelope at ca. 1050 cm(-1) of pure liquid DMSO are assigned to monomers, dimers and higher aggregates of DMSO. The appearance of a new band at 1024 cm(-1), whose intensity shows large dependence on the FA concentration, is assigned to a FA-DMSO adduct. This has been possible due to the two H-bond donor sites of FA and the strong donor character of DMSO that become the environment propitious for the donor-acceptor reaction. Quantitative analysis performed in the SO stretching region in the binary mixtures gives a 1:1 stoichiometry in this adduct in the limit of infinite dilution. This proportion is in full agreement with our previous determination for the FA-ACN adduct. The experimental evidence of the 1:1 FA-DMSO adduct is presented for the first time using Raman spectroscopy. The results described here open new possibilities to study the acid-base reactions nature of FA adducts.
Spectrochim Acta A Mol Biomol Spectrosc 2007 Jul
PMID:Lewis acid-base adducts: a quantitative Raman analysis of formamide and dimethylsulfoxide mixtures. 1702 98

Mutations in the Neurofibromatosis type 2 tumor suppressor gene that encodes Schwannomin causes formation of benign schwannomas. Schwannoma cells lose their characteristic bipolar shape and become rounded with excessive ruffling membranes. Schwannomin is phosphorylated at serine 518 (S518) by p21 activated kinase (Pak). Unphosphorylated schwannomin is associated with growth inhibition but little is known about the function of the phosphorylated form, or the molecular events leading to its phosphorylation. Here, we report in SCs that schwannomin S518 phosphorylation requires binding to paxillin and targeting to the plasma membrane. Phospho-S518-schwannomin is enriched in the peripheral-most aspects of membrane specializations where paxillin, activated Pak, Cdc42 but not Rac are highly expressed. Schwannomin and Pak phosphorylation levels are not reduced in response to lowering Rac-GTP levels with NSC23766. Expression of schwannomin S518A/D-GFP variants each distinctively altered Schwann cell shape and polarity. These results are consistent with tight spatial regulation of S518 phosphorylation at the plasma membrane in a paxillin and Cdc42-Pak dependent manner that leads to local reorganization of the SC cytoskeleton.
Mol Cell Neurosci 2007 Feb
PMID:Phosphorylation of the NF2 tumor suppressor in Schwann cells is mediated by Cdc42-Pak and requires paxillin binding. 1717 65

Merlin, the product of the NF2 tumor suppressor gene, is closely related to the ERM (ezrin, radixin, moesin) proteins, which provide anchorage between membrane proteins and the underlying cortical cytoskeleton; all four proteins are members of the band 4.1 superfamily. Despite their similarity, the subcellular distributions and functional properties of merlin and the ERM proteins are largely distinct. Upon cell-cell contact merlin prevents internalization of and signaling from the epidermal growth factor receptor (EGFR) by sequestering it into an insoluble membrane compartment. Here we show that the extreme amino (N) terminus directs merlin biochemically to an insoluble membrane compartment and physically to the cortical actin network, with a marked concentration along cell-cell boundaries. This insoluble-membrane distribution is required for the growth-suppressing function of merlin and for the functional association of merlin with EGFR and other membrane receptors. Our data support a model whereby locally activated merlin sequesters membrane receptors such as EGFR at the cortical network, contributing to the long-held observation that the cortical actin cytoskeleton can control the lateral mobility of and signaling from certain membrane receptors.
Mol Cell Biol 2008 Feb
PMID:Localization to the cortical cytoskeleton is necessary for Nf2/merlin-dependent epidermal growth factor receptor silencing. 1808 84


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