The Function of Lysyl-tRNA Synthetase and Ap4A as Signaling Regulators of MITF Activity in FcϵRI-Activated Mast Cells

Lee, Yu Nee; Nechushtan, Hovav; Figov, Navah; Razin, Ehud

doi:10.1016/s1074-7613(04)00020-2

Cited by 165 publications

(189 citation statements)

References 34 publications

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“…Indeed, in vitro studies indicated that human HINT1 can bind various nucleotides, including AMP, ADP, and the diadenosine polyphosphates Ap 3 A and Ap 4 A (Lima et al, 1997;Lee et al, 2004). Rabbit HINT1 also binds several purine nucleosides and nucleoside 5 0 -phosphates .…”

Section: Introductionmentioning

confidence: 99%

Hint1 is a haplo-insufficient tumor suppressor in mice

et al. 2005

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The HINT1 protein, a member of the histidine triad (HIT) family, is highly conserved in diverse species and ubiquitously expressed in mammalian tissues. However, its precise function in mammalian cells is not known. As a result of its structural similarity to the tumor-suppressor protein FHIT, we used homozygous-deleted Hint1 mice to study its role in tumorigenesis. We discovered that after 2 to 3 years of age the spontaneous tumor incidence in Hint1 À/À mice was significantly greater than that in wildtype Hint1 þ / þ mice (Po0.05). Using a well-established mouse model of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis we found a marked and significant (Po0.05) increase in the incidence of mammary and ovarian tumors in both, Hint1 À/À and þ /À mice versus þ / þ mice. The Hint1 À/À and þ /À mice had similar tumor incidence and similar tumor histologies. Therefore, deletion of Hint1 in mice enhances both spontaneous tumor development and susceptibility to tumor induction by DMBA. In addition, since the Hint1 þ /À tumors retained expression of the unmutated wildtype allele, Hint1 is haplo-insufficient with respect to tumor suppression in this model system.

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Section: Introductionmentioning

confidence: 99%

Hint1 is a haplo-insufficient tumor suppressor in mice

et al. 2005

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“…Fhit, like all members of the HIT superfamily, has proven nucleotide-binding and nucleotide-hydrolyzing activity preferentially for diadenosine polyphosphates (Ap n A, n ϭ 3 or 4) (8). Ap n As have been identified as intracellular signaling molecules that are synthesized in side reactions of certain tRNA synthetases under stress conditions (9). Site-directed mutagenesis of the central histidine 96 of the HIT to asparagine generates a mutant Fhit protein that although enzymatically dead still shows tumor suppressive and proapoptotic activity (10,11).…”

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confidence: 99%

The tumor suppressor Fhit acts as a repressor of β-catenin transcriptional activity

Weiske

Albring

Huber

2007

Proc. Natl. Acad. Sci. U.S.A.

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The Fra3B locus on chromosome 3p14.2 targeting the fragile histidine triad (Fhit) gene represents one of the most common fragile sites of the human genome and is associated with early preneoplastic and malignant disorders in multiple human tumors. Fhit was classified as a tumor suppressor; however, the molecular mechanisms of its function are not well established. Here, we report that Fhit associates with the lymphoid enhancer-binding factor 1/T cell factor/␤-catenin complex by directly binding to ␤-catenin, a major player in the canonical Wnt pathway that is deregulated in numerous forms of human cancer. In binding to the ␤-catenin C-terminal domain, Fhit represses transcription of target genes such as cyclin D1, axin2, MMP-14, and survivin. Knockdown of Fhit reversed this effect, whereas this reversal was not detectable when ␤-catenin was knocked down simultaneously. The Fhit enzymatic activity as a diadenosine-polyphosphate hydrolase is not required for the down-regulation of ␤-catenin-mediated transcription as examined with an enzymatic inactive Fhit-H96N protein. ChIPs revealed recruitment of Fhit/␤-catenin complexes to target gene promoters. In soft agar assays Fhit and ␤-catenin are involved in regulation of anchorage-independent growth. These observations assign to the tumor suppressor Fhit an unexpected role in the regulation of ␤-catenin-mediated gene transcription.histidine triad ͉ T cell factor ͉ lymphoid enhancer-binding factor 1

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“…Second, it can synthesize diadenosine polyphosphates in addition to its aminoacylation activity (13,14). This activity was recently shown to play a role in transcription control through microphthalmia transcription factor (15). Third, mammalian KRS is a component of the multi-ARS complex (16), specifically interacting with an auxiliary factor, p38 (17,18), and contains a lysine-rich N-terminal extension that binds tRNA and enhances the catalytic efficiency (19,20).…”

mentioning

confidence: 99%

Human lysyl-tRNA synthetase is secreted to trigger proinflammatory response

Park

Kim

Min

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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144

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Although aminoacyl-tRNA synthetases (ARSs) are essential for protein synthesis, they also function as regulators and signaling molecules in diverse biological processes. Here, we screened 11 different human ARSs to identify the enzyme that is secreted as a signaling molecule. Among them, we found that lysyl-tRNA synthetase (KRS) was secreted from intact human cells, and its secretion was induced by TNF-␣. The secreted KRS bound to macrophages and peripheral blood mononuclear cells to enhance the TNF-␣ production and their migration. The mitogen-activated protein kinases, extracellular signal-regulated kinase and p38 mitogen-activated protein kinase, and G␣i were determined to be involved in the signal transduction triggered by KRS. All of these activities demonstrate that human KRS may work as a previously uncharacterized signaling molecule, inducing immune response through the activation of monocyte͞macrophages.aminoacyl-tRNA synthetase ͉ cytokine ͉ TNF-␣ ͉ immune response ͉ cell migration

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The Function of Lysyl-tRNA Synthetase and Ap4A as Signaling Regulators of MITF Activity in FcϵRI-Activated Mast Cells

Cited by 165 publications

References 34 publications

Hint1 is a haplo-insufficient tumor suppressor in mice

Hint1 is a haplo-insufficient tumor suppressor in mice

The tumor suppressor Fhit acts as a repressor of β-catenin transcriptional activity

Human lysyl-tRNA synthetase is secreted to trigger proinflammatory response

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