title: MAGED1 is a novel regulator of a select subset of bHLH PAS transcription factors.
abstract: Transcription factors of the basic helix-loop-helix (bHLH) PER-ARNT-SIM (PAS) family generally have critical and nonredundant biological roles, but some bHLH PAS proteins compete for common cofactors or recognise similar DNA elements. Identifying factors that regulate function of bHLH PAS proteins, particularly in cells where multiple family members are coexpressed, is important for understanding bHLH PAS factor biology. This study identifies and characterises a novel interaction between melanoma-associated antigen D1 (MAGED1) and select members of the bHLH PAS transcription factor family. MAGED1 binds and positively regulates the transcriptional activity of family members SIM1, SIM2, NPAS4 and ARNT2, but does not interact with AhR, HIF1α and ARNT. This interaction is mediated by PAS repeat regions which also form the interface for bHLH PAS dimerisation, and accordingly MAGED1 is not found in complex with bHLH PAS dimers. We show that MAGED1 does not affect bHLH PAS protein levels and cannot be acting as a coactivator of transcriptionally active heterodimers, but rather appears to interact with nascent bHLH PAS proteins in the cytoplasm to enhance their function prior to nuclear import. As a selective regulator, MAGED1 may play an important role in the biology of these specific factors and in general bHLH PAS protein dynamics.
authors.affiliation: Department of Molecular and Cellular Biology, University of Adelaide, Australia. adrienne.sullivan@adelaide.edu.au.
authors.forename: Adrienne E
authors.initials: AE
authors.lastname: Sullivan
authors.affiliation: Department of Molecular and Cellular Biology, University of Adelaide, Australia.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Peet
authors.affiliation: Department of Molecular and Cellular Biology, University of Adelaide, Australia.
authors.forename: Murray L
authors.initials: ML
authors.lastname: Whitelaw
mesh_terms: D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000145:classification / Q000378:metabolism*; D055550:Protein Stability; D018336:Receptors, Aryl Hydrocarbon / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D018336:Receptors, Aryl Hydrocarbon; D011994:Recombinant Proteins; D012097:Repressor Proteins; C111235:AHR protein, human; C497396:ARNT protein, human; C490989:ARNT2 protein, human; C497442:HIF1A protein, human; C120897:MAGED1 protein, human; C481603:NPAS4 protein, human; C491094:SIM1 protein, human; C417032:SIM2 protein, human; C116037:PAS domain kinases
keywords: NPAS4; SIM1; SIM2; protein-protein interaction; transcription factor regulation