title: Miz-1 and Max compete to engage c-Myc: implication for the mechanism of inhibition of c-Myc transcriptional activity by Miz-1.
abstract: c-Myc is a basic helix-loop-helix leucine zipper (b-HLH-LZ) transcription factor deregulated in the majority of human cancers. As a heterodimer with Max, another b-HLH-LZ transcription factor, deregulated and persistent c-Myc accumulates at transcriptionally active promoters and enhancers and amplifies transcription. This leads to the so-called transcriptional addiction of tumor cells. Recent studies have showed that c-Myc transcriptional activities can be reversed by its association with Miz-1, a POZ transcription factor containing 13 classical zinc fingers. Although evidences have led to suggest that c-Myc interacts with both Miz-1 and Max to form a ternary repressive complex, earlier evidences also suggest that Miz-1 and Max may compete to engage c-Myc. In such a scenario, the Miz-1/c-Myc complex would be the entity responsible for the inhibition of c-Myc transcriptional amplification. Considering the implications of the Miz-1/c-Myc interaction, it is highly important to solve this duality. While two potential c-Myc interacting domains (hereafter termed MID) have been identified in Miz-1 by yeast two-hybrid, with the b-HLH-LZ as a bait, the biophysical characterization of these interactions has not been reported so far. Here, we report that the MID located between the 12th and 13th zinc finger of Miz-1 and the b-HLH-LZ of Max compete to form a complex with the b-HLH-LZ of c-Myc. Our results support the notion that the repressive action of Miz-1 on c-Myc does not rely on the formation of a ternary complex. The implications of these observations for the mechanism of inhibition of c-Myc transcriptional activity by Miz-1 are discussed. Proteins 2017; 85:199-206. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Département de Biochimie, Institut de Pharmacologie de Sherbrooke, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, J1H 5N4, Canada.|PROTEO; Regroupement Stratégique sur la Fonction, la Structure et l'Ingénierie des Protéines, Université Laval, Québec, G1V 0A6, Canada.|GRASP; Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Québec, H3G 0B1, Canada.
authors.forename: Mikaël
authors.initials: M
authors.lastname: Bédard
authors.affiliation: Département de Biochimie, Institut de Pharmacologie de Sherbrooke, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, J1H 5N4, Canada.|PROTEO; Regroupement Stratégique sur la Fonction, la Structure et l'Ingénierie des Protéines, Université Laval, Québec, G1V 0A6, Canada.|GRASP; Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Québec, H3G 0B1, Canada.
authors.forename: Loïka
authors.initials: L
authors.lastname: Maltais
authors.affiliation: Département de Biochimie, Institut de Pharmacologie de Sherbrooke, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, J1H 5N4, Canada.|PROTEO; Regroupement Stratégique sur la Fonction, la Structure et l'Ingénierie des Protéines, Université Laval, Québec, G1V 0A6, Canada.|GRASP; Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Québec, H3G 0B1, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Montagne
authors.affiliation: Département de Biochimie, Institut de Pharmacologie de Sherbrooke, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, J1H 5N4, Canada.|PROTEO; Regroupement Stratégique sur la Fonction, la Structure et l'Ingénierie des Protéines, Université Laval, Québec, G1V 0A6, Canada.|GRASP; Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Québec, H3G 0B1, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lavigne
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002942:Circular Dichroism; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051741:Kruppel-Like Transcription Factors; C499330:MAX protein, human; D016271:Proto-Oncogene Proteins c-myc; D011994:Recombinant Proteins; C107961:ZBTB17 protein, human
keywords: Max; Miz-1; NMR; b-HLH-LZ; c-Myc; circular dichroism