title: HIF-1alpha induces MXI1 by alternate promoter usage in human neuroblastoma cells.
abstract: Adaptation to low oxygen conditions is essential for maintaining homeostasis and viability in oxygen-consuming multi-cellular tissues, including solid tumors. Central in these processes are the hypoxia-inducible transcription factors, HIF-1 and HIF-2, controlling genes involved in e.g. glucose metabolism and neovascularization. Tumor hypoxia and HIF expression have also been associated with a dedifferentiated phenotype and increased aggressiveness. In this report we show that the MAX interactor-1 (MXI1) gene is directly regulated by HIF proteins in neuroblastoma and breast cancer cells. HIF-binding and transactivation were detected within MXI1 gene regulatory sequences in the vicinity of the MXI1-0 promoter, leading to rapid induction of the alternate MXI1-0 isoform followed by a long-term induction of both the MXI1-0 and MXI1 isoforms. Importantly, knock-down of MXI1 had limited effect on MYC/MYCN activity under hypoxia, an observation that might be related to the different functional attributes of the two MXI1 isoforms.
authors.affiliation: Center for Molecular Pathology, Department of Laboratory Medicine, Lund University, University Hospital MAS, Entrance 78, S-20502 Malmö, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Löfstedt
authors.forename: Erik
authors.initials: E
authors.lastname: Fredlund
authors.forename: Rosa
authors.initials: R
authors.lastname: Noguera
authors.forename: Samuel
authors.initials: S
authors.lastname: Navarro
authors.forename: Linda
authors.initials: L
authors.lastname: Holmquist-Mengelbier
authors.forename: Siv
authors.initials: S
authors.lastname: Beckman
authors.forename: Sven
authors.initials: S
authors.lastname: Påhlman
authors.forename: Håkan
authors.initials: H
authors.lastname: Axelson
mesh_terms: D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D016259:Genes, myc; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; C497442:HIF1A protein, human; C079440:MXI1 protein, human