title: The heteromeric transcription factor GABP activates the ITGAM/CD11b promoter and induces myeloid differentiation.
abstract: The heteromeric transcription factor GA-binding protein (GABP) consists of two subunits, the alpha subunit (GABPA) carrying the DNA-binding ETS domain, and the beta subunit (GABPB1) harbouring the transcriptional activation domain. GABP is involved in haematopoietic stem cell maintenance and differentiation of myeloid and lymphoid lineages in mice. To elucidate the molecular function of GABP in human haematopoiesis, the present study addressed effects of ectopic overexpression of GABP focussing on the myeloid compartment. Combined overexpression of GABPA and GABPB1 caused a proliferation block in cell lines and drastically reduced the colony-forming capacity of murine lineage-negative cells. Impaired proliferation resulted from perturbed cellular cycling and induction of myeloid differentiation shown by surface markers and myelomonocytic morphology of U937 cells. Depending on the dosage and functional integrity of GABP, ITGAM expression was induced. ITGAM encodes CD11b, the alpha subunit of integrin Mac-1, whose beta subunit, ITGB2/CD18, was already described to be regulated by GABP. Finally, Shield1-dependent proteotuning, luciferase reporter assays and chromatin immunoprecipitation showed that GABP activates the ITGAM/CD11b promoter via three binding sites close to the translational start site. In conclusion, the present study supports the crucial role of GABP in myeloid cell differentiation and identified ITGAM/CD11b as a novel GABP target gene.
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: ripperger.tim@mh-hannover.de.
authors.forename: Tim
authors.initials: T
authors.lastname: Ripperger
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: manukjan.georgi@mh-hannover.de.
authors.forename: Georgi
authors.initials: G
authors.lastname: Manukjan
authors.affiliation: Institute of Experimental Haematology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: meyer.johann@mh-hannover.de.
authors.forename: Johann
authors.initials: J
authors.lastname: Meyer
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: wolter.sabine@mh-hannover.de.
authors.forename: Sabine
authors.initials: S
authors.lastname: Wolter
authors.affiliation: Institute of Experimental Haematology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address: schambach.axel@mh-hannover.de.
authors.forename: Axel
authors.initials: A
authors.lastname: Schambach
authors.affiliation: Institute of Virology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: bohne.jens@mh-hannover.de.
authors.forename: Jens
authors.initials: J
authors.lastname: Bohne
authors.affiliation: Institute of Experimental Haematology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: ute.modlich@pei.de.
authors.forename: Ute
authors.initials: U
authors.lastname: Modlich
authors.affiliation: Institute of Experimental Haematology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: li.zhixiong@mh-hannover.de.
authors.forename: Zhixiong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: skawran.britta@mh-hannover.de.
authors.forename: Britta
authors.initials: B
authors.lastname: Skawran
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: schlegelberger.brigitte@mh-hannover.de.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: steinemann.doris@mh-hannover.de.
authors.forename: Doris
authors.initials: D
authors.lastname: Steinemann
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000235:genetics*; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D051268:GA-Binding Protein Transcription Factor / Q000235:genetics / Q000502:physiology*; D018628:Gene Dosage; D006801:Humans; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology*; D011401:Promoter Regions, Genetic
chemical_list: D039481:CD11b Antigen; D051268:GA-Binding Protein Transcription Factor; C509295:ITGAM protein, human
keywords: CD11b; GABP; ITGAM; Myeloid differentiation; Shield1-dependent proteotuning; Transcription factor