Nonconventional Involvement of LysRS in the Molecular Mechanism of USF2 Transcriptional Activity in FcεRI-Activated Mast Cells

Lee, Yu Nee; Razin, Ehud

doi:10.1128/mcb.25.20.8904-8912.2005

Cited by 63 publications

(77 citation statements)

References 45 publications

(62 reference statements)

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“…Thus, in mast cells, HINT1 inhibits the activities of the bHLH transcription factors MITF and USF2 by binding directly to these proteins (16,17), and in SW480 cells, HINT1 inhibits h-catenin/TCF4 activity by binding to the associated proteins Pontin and Reptin (18). The latter study also found that because of this effect, HINT1 also inhibits the transcription of cyclin D1 and expression of the cyclin D1 protein (18).…”

Section: Discussionsupporting

confidence: 57%

“…Since then, other investigators have obtained evidence that the HINT1 protein can also interact with other proteins, which include the product of the ATDC gene (13), which seems to play a role in cellular responses to ionizing radiation; cyclin-dependent kinase 7 (14), which functions in growth control and transcriptional regulation; the human mu-opioid receptor, which is a Gprotein-coupled receptor that mediates analgesia, euphoria, and other important central and peripheral neurologic functions (15); the transcription factor microphthalmia also called MITF (16), which plays an important role in mast cell and melanocyte growth; the ubiquitously expressed transcription factor USF2 (17); and Pontin and Reptin (18), which complex with h-catenin and thereby regulate the h-catenin/TCF4 signaling pathway. Indeed, the latter study indicated that overexpression of HINT1 significantly inhibited both h-catenin/TCF4 and cyclin D1 transcription factor activity in SW480 colon cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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Hint1 Inhibits Growth and Activator Protein-1 Activity in Human Colon Cancer Cells

Wang

Zhang

et al. 2007

Cancer Research

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There is accumulating evidence that histidine triad (HIT) nucleotide-binding protein 1 (HINT1), a member of the evolutionary highly conserved HIT protein super family, is a novel tumor suppressor. However, the mechanism of action of HINT1 with respect to tumor suppression is not known. In the present study, we found that a series of human colon cancer cell lines displayed various levels of expression of HINT1, with a very low level in SW480 cells. This cell line also displayed partial methylation of the promoter region of the Hint1 gene, and treatment of these cells with 5-azadeoxycitidine increased expression of Hint1 mRNA and protein. Therefore, the decreased expression of HINT1 in SW480 cells seems to be due to epigenetic silencing. Increased expression of HINT1 in these cells, using a retrovirus vector (pLNCX2) that encodes either wild-type (WT) Hint1 or a point mutant (His 112 /Asn 112 ) of Hint1, inhibited the proliferation of SW480 cells. Because of the important role of the activator protein-1 (AP-1) transcription factor in cancer cells, we examined possible effects of HINT1 on AP-1 transcription factor activity in SW480 cells transfected with an AP-1-luciferase reporter. We found that cotransfection with a pHA-Hint1 plasmid DNA significantly inhibited this activity. Studies with inhibitors indicated that AP-1 activity in SW480 cells requires the activity of c-Jun NH 2 -terminal kinase (JNK) 2 and not JNK1. Cotransfection with the Hint1 plasmid DNA also inhibited AP-1-luciferase reporter activity in WT mouse embryo fibroblast (MEF) studies, and studies with JNK1 deleted or JNK2 deleted MEFs confirmed the essential role for JNK2, but not JNK1, in mediating AP-1 activity. Recent studies indicate that the protein plenty of SH3 (POSH) provides a scaffold that enhances JNK activity. We found that cotransfection of a plasmid DNA encoding POSH stimulated the phosphorylation of c-Jun and also AP-1 reporter activity, and cotransfection with Hint1 inhibited both of these activities. Furthermore, coimmunoprecipitation studies provided evidence that HINT1 forms an in vivo complex with POSH and JNK. These results suggest that HINT1 inhibits AP-1 activity by binding to a POSH-JNK2 complex, thus inhibiting the phosphorylation of c-Jun. This effect could contribute to the tumor suppressor activity of HINT1. [Cancer Res 2007;67(10):4700-8]

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Section: Discussionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Hint1 Inhibits Growth and Activator Protein-1 Activity in Human Colon Cancer Cells

Wang

Zhang

et al. 2007

Cancer Research

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“…We have shown that both MITF and another bHLH-Zip transcription factor, upstream stimulatory factor 2 (USF2) form a tertiary complex with their inhibitor histidine triad nucleotide-binding 1 (Hint-1) and with lysyl-tRNA synthetase (LysRS) (16,17). Furthermore, we have shown that Ap 4 A can bind to Hint-1 and cause its release from MITF and from USF2 (16,17).…”

mentioning

confidence: 95%

Diadenosine Tetraphosphate Hydrolase Is Part of the Transcriptional Regulation Network in Immunologically Activated Mast Cells

Carmi-Levy

Yannay-Cohen

Kay

et al. 2008

Molecular and Cellular Biology

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“…Hint1 has also been associated with transcription factors such as, TFIIH (11), MITF (12,13), and USF2 (14). In addition, the interactions between MITF and USF2 appear to be mediated by LysRS (13)(14)(15).…”

mentioning

confidence: 99%

Engineered Monomeric Human Histidine Triad Nucleotide-binding Protein 1 Hydrolyzes Fluorogenic Acyl-adenylate and Lysyl-tRNA Synthetase-generated Lysyl-adenylate

Chou

Tikh

Horta

et al. 2007

Journal of Biological Chemistry

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Hint1 is a homodimeric protein and member of the ubiquitous HIT superfamily. Hint1 catalyzes the hydrolysis of purine phosphoramidates and lysyl-adenylate generated by lysyl-tRNA synthetase (LysRS). To determine the importance of homodimerization on the biological and catalytic activity of Hint1, the dimer interface of human Hint1 (hHint1) was destabilized by replacement of Val 97 of hHint1 with Asp, Glu, or Arg. The mutants were shown to exist as monomers in solution by a combination of size exclusion chromatograph, static light scattering, and chemically induced dimerization studies. Circular dichroism studies revealed little difference between the stability of the V97D, V97E, and wild-type hHint1. Relative to wild-type and the V97E mutant, however, significant perturbation of the V97D mutant structure was observed. hHint1 was shown to prefer 3-indolepropionic acyl-adenylate (AIPA) over tryptamine adenosine phosphoramidate monoester (TpAd). Wild-type hHint1 was found to be 277-and 1000-fold more efficient (k cat /K m values) than the V97E and V97D mutants, respectively. Adenylation of wildtype, V97D, and V97E hHint1 by human LysRS was shown to correlate with the mutant k cat /K m values using 3-indolepropionic acyl-adenylate as a substrate, but not tryptamine adenosine phosphoramidate monoester. Significant perturbations of the active site residues were not detected by molecular dynamics simulations of the hHint1s. Taken together, these results demonstrate that for hHint1; 1) the efficiency (k cat / K m ) of acylated AMP hydrolysis, but not maximal catalytic turnover (k cat ), is dependent on homodimerization and 2) the hydrolysis of lysyl-AMP generated by LysRS is not dependent on homodimerization if the monomer structure is similar to the wild-type structure.Histidine triad nucleotide-binding proteins (Hint) 2 are members of the histidine triad (HIT) protein superfamily of nucleotidyltransferases and hydrolyases (1). HIT proteins are named for the conserved nucleotide binding motif containing the sequence His-X-His-X-His-XX, in which X is a hydrophobic amino acid. The HIT proteins have been classified into three subfamilies according to their enzymatic function, sequence composition, and structural similarity; the Hint branch, the fragile histidine triad (Fhit) branch, and the galactose-1-phosphate uridyltransferase (GalT) branch (1).The Hint branch is the most ancient and can be found in Archaea, Bacteria, and Eukaryotae. Hints are homodimeric proteins that have been found to be purine phosphoramidases (2-5). Recently, we have demonstrated that lysyl-adenylate (lysyl-AMP) generated by bacterial and human lysyl-tRNA synthetases (LysRS) are also substrates for the respective bacterial and human Hints (6). Escherichia coli hinT knock-out mutants exhibited salt-dependent cell growth, whereas Hint1 knock-out mice have an increased susceptibility to 7, 12-dimethylbenz[a]anthracene (DMBA)-induced ovarian and mammary tumors by the carcinogen DMBA and increased incidence of spontaneous tumors (2,7,8). In addition,...

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Nonconventional Involvement of LysRS in the Molecular Mechanism of USF2 Transcriptional Activity in FcεRI-Activated Mast Cells

Cited by 63 publications

References 45 publications

Hint1 Inhibits Growth and Activator Protein-1 Activity in Human Colon Cancer Cells

Hint1 Inhibits Growth and Activator Protein-1 Activity in Human Colon Cancer Cells

Diadenosine Tetraphosphate Hydrolase Is Part of the Transcriptional Regulation Network in Immunologically Activated Mast Cells

Engineered Monomeric Human Histidine Triad Nucleotide-binding Protein 1 Hydrolyzes Fluorogenic Acyl-adenylate and Lysyl-tRNA Synthetase-generated Lysyl-adenylate

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