NATH, a novel gene overexpressed in papillary thyroid carcinomas

Fluge, Øystein; Bruland, Ove; Akslen, Lars A.; Varhaug, Jan Erik; Lillehaug, Johan R.

doi:10.1038/sj.onc.1205687

Cited by 50 publications

(46 citation statements)

References 39 publications

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“…The human NATH gene was identified and demonstrated to be overexpressed in papillary thyroid carcinomas, especially in clinically aggressive and undifferentiated tumours (Fluge et al, 2002). These in vivo observations point to a possible growth advantage of tumour cells overexpressing the NATH gene.…”

Section: Introductionmentioning

confidence: 84%

Induction of apoptosis in human cells by RNAi-mediated knockdown of hARD1 and NATH, components of the protein N-α-acetyltransferase complex

et al. 2006

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Protein N-e-acetylation is recognized as an important modification influencing many biological processes, and protein deacetylase inhibitors leading to N-e-hyperacetylation of histones are being clinically tested for their potential as anticancer drugs. In contrast to N-eacetyltransferases, the N-a-acetyltransferases transferring acetyl groups to the a-amino groups of protein N-termini have only been briefly described in mammalians. Human arrest defective 1 (hARD1), the only described human enzyme in this class, complexes with N-acetyltransferase human (NATH) and cotranslationally transfers acetyl groups to the N-termini of nascent polypeptides. Here, we demonstrate that knockdown of NATH and/or hARD1 triggers apoptosis in human cell lines. Knockdown of hARD1 also sensitized cells to daunorubicin-induced apoptosis, potentially pointing at the NATH-hARD1 acetyltransferase complex as a novel target for chemotherapy. Our results argue for an essential role of the NATH-hARD1 complex in cell survival and underscore the importance of protein N-aacetylation in mammalian cells.

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Section: Introductionmentioning

confidence: 84%

Induction of apoptosis in human cells by RNAi-mediated knockdown of hARD1 and NATH, components of the protein N-α-acetyltransferase complex

et al. 2006

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“…From a cancer standpoint, it is of interest to note that the mouse N-terminal acetyltransferase is implicated in vascular development (33)(34)(35) and therefore may play an active role in angiogenesis. The human orthologue, tubedown-100, also termed NATH or Ga19, has been shown to be implicated in transcription of the osteocalcin gene (36) and is overexpressed in papillary thyroid carcinoma (37) and gastric cancer (38). The role, if any, that ARD1 plays in these processes as a NAT-interacting partner remains unstudied.…”

Section: Discussionmentioning

confidence: 99%

Arrest-defective-1 Protein, an Acetyltransferase, Does Not Alter Stability of Hypoxia-inducible Factor (HIF)-1α and Is Not Induced by Hypoxia or HIF

Bilton

Mazure

Trottier

et al. 2005

Journal of Biological Chemistry

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The hypoxia-inducible factor (HIF) is a key player in a transcriptional pathway that controls the hypoxic response of mammalian cells. Post-translational modification of the ␣ subunit of HIF determines its half-life and activity. Among the multiple reported modifications, acetylation, by an acetyltransferase termed arrest-defective-1 protein (ARD1), has been reported to decrease HIF-1␣ stability and therefore impact on hypoxic gene expression. In contrast, we report that both overexpression and silencing of ARD1 had no impact on the stability of HIF-1␣ or -2␣ and that cells silenced for ARD1 maintained hypoxic nuclear localization of HIF-1␣. In addition, we show that the ARD1 mRNA and protein levels are not regulated by hypoxia in several human tumor cell lines, including cervical adenocarcinoma HeLa cells, fibrosarcoma HT1080 cells, adenovirustransformed human kidney HEK293 cells, and human breast cancer MCF-7 cells. Using two model systems ((a) wild-type and HIF-1␣-null mouse embryo fibroblasts and (b) HeLa cells silenced for HIF-1␣ or -2␣ by RNA interference), we demonstrate that the level of expression of the ARD1 protein is independent of HIF-1␣ and -2␣. We also demonstrate that ARD1 is a stable, predominantly cytoplasmic protein expressed in a broad range of tissues, tumor cell lines, and endothelial cells. Taken together, our findings demonstrate that ARD1 has limited, if any, impact on the HIF signaling pathway.

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“…1. A second polyclonal anti-Tbdn rabbit antibody was raised against a peptide corresponding to the amino acid sequence 755-766 (LKRNSDSLPHRL) of human Tbdn100 (Fluge et al, 2002) to which a cysteine residue was added to the amino terminus to facilitate coupling to keyhole limpet hemocyanin (KLH; Pierce, Rockford, IL). Specificity of this antiserum was demonstrated by its ability to immunoprecipitate recombinant Tbdn and by competition of the western blot signal for Tbdn with the Tbdn blocking peptide C755-766 (data not shown).…”

Section: Antibodiesmentioning

confidence: 99%

Tubedown associates with cortactin and controls permeability of retinal endothelial cells to albumin

Paradis

Islam

Tucker

et al. 2008

Journal of Cell Science

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Tubedown (Narg1, Tbdn), a member of the Nat1 family of proteins, associates with the acetyltransferase Ard1 and exerts an angiostatic function in adult retinal-blood-vessel homeostasis. The purpose of the present study was to gain a better understanding of the nature of the Tbdn protein complex and how it might exert a homeostatic influence on blood vessels. Immunoprecipitation of Tbdn from endothelial cells followed by gel electrophoresis and liquid-chromatography–tandem-mass-spectrometry identified the actin-cytoskeleton-binding protein cortactin as a co-immunopurifying species. Western blotting confirmed the association between Tbdn and cortactin. Immunofluorescence confocal microscopy revealed that Tbdn colocalizes with cortactin and F-actin in cytoplasmic regions and at the cortex of cultured endothelial cells. Because cortactin is known to regulate cellular permeability through its interaction with the actin cytoskeleton, a process that is crucial for endothelial cell homeostasis, the role of Tbdn on endothelial cell permeability was examined. Knockdown of Tbdn expression in endothelial cells led to the co-suppression of Ard1 protein expression and to a significant increase in cellular permeability measured by the transit of FITC-albumin across the cellular monolayer. Furthermore, the proliferative retinal neovascularization and thickening resulting from induction of Tbdn knockdown in endothelium in transgenic mice was associated with a significant increase in extravasation or leakage of albumin from abnormal retinal blood vessels in vivo. These results provide evidence that an association occurs between Tbdn and cortactin, and that Tbdn is involved in the regulation of retinal-endothelial-cell permeability to albumin. This work implicates a functional role for Tbdn in blood-vessel permeability dynamics that are crucial for vascular homeostasis.

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NATH, a novel gene overexpressed in papillary thyroid carcinomas

Cited by 50 publications

References 39 publications

Induction of apoptosis in human cells by RNAi-mediated knockdown of hARD1 and NATH, components of the protein N-α-acetyltransferase complex

Induction of apoptosis in human cells by RNAi-mediated knockdown of hARD1 and NATH, components of the protein N-α-acetyltransferase complex

Arrest-defective-1 Protein, an Acetyltransferase, Does Not Alter Stability of Hypoxia-inducible Factor (HIF)-1α and Is Not Induced by Hypoxia or HIF

Tubedown associates with cortactin and controls permeability of retinal endothelial cells to albumin

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