title: The intracellular domain of teneurin-1 induces the activity of microphthalmia-associated transcription factor (MITF) by binding to transcriptional repressor HINT1.
abstract: Teneurins are large type II transmembrane proteins that are necessary for the normal development of the CNS. Although many studies highlight the significance of teneurins, especially during development, there is only limited information known about the molecular mechanisms of function. Previous studies have shown that the N-terminal intracellular domain (ICD) of teneurins can be cleaved at the membrane and subsequently translocates to the nucleus, where it can influence gene transcription. Because teneurin ICDs do not contain any intrinsic DNA binding sequences, interaction partners are required to affect transcription. Here, we identified histidine triad nucleotide binding protein 1 (HINT1) as a human teneurin-1 ICD interaction partner in a yeast two-hybrid screen. This interaction was confirmed in human cells, where HINT1 is known to inhibit the transcription of target genes by directly binding to transcription factors at the promoter. In a whole transcriptome analysis of BS149 glioblastoma cells overexpressing the teneurin-1 ICD, several microphthalmia-associated transcription factor (MITF) target genes were found to be up-regulated. Directly comparing the transcriptomes of MITF versus TEN1-ICD-overexpressing BS149 cells revealed 42 co-regulated genes, including glycoprotein non-metastatic b (GPNMB). Using real-time quantitative PCR to detect endogenous GPNMB expression upon overexpression of MITF and HINT1 as well as promoter reporter assays using GPNMB promoter constructs, we could demonstrate that the teneurin-1 ICD binds HINT1, thus switching on MITF-dependent transcription of GPNMB.
authors: From the Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland and the Faculty of Science, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
authors: Jonas
authors: J
authors: Schöler
authors: From the Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland and.
authors: Jacqueline
authors: J
authors: Ferralli
authors: From the Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland and.
authors: Stéphane
authors: S
authors: Thiry
authors: From the Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland and the Faculty of Science, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland ruth.chiquet@fmi.ch.
authors: Ruth
authors: R
authors: Chiquet-Ehrismann
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D015870:Gene Expression; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D019063:Tenascin / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: C503042:GPNMB protein, human; C063306:HINT1 protein, human; C497234:MITF protein, human; D008562:Membrane Glycoproteins; D051739:Microphthalmia-Associated Transcription Factor; D009419:Nerve Tissue Proteins; D019063:Tenascin; C120530:teneurin-1
keywords: BEX1; GPNMB; Glioblastoma; MACF1; Microarray; ODZ; Protein-Protein Interaction; Receptor; TENM1; Transcription Repressor
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