title: Hoxb8 regulates expression of microRNAs to control cell death and differentiation.
abstract: Hoxb8 overexpression immortalises haematopoietic progenitor cells in a growth-factor-dependant manner and co-operates with interleukin-3 (IL-3) to cause acute myeloid leukaemia. To further understand how Hoxb8 contributes to myeloid cell immortalisation, we generated IL-3-dependant myeloid cells expressing Hoxb8 under the control of an inducible promoter. Downregulation of Hoxb8, in the presence of IL-3, caused cell-cycle arrest and apoptosis in the majority of cells. Apoptosis was dependant on Bax and Bak and, in part, on Bim, which was repressed by Hoxb8. Deletion of the miR-17∼92 seed sequences in the Bim 3'UTR abolished Hoxb8-dependant regulation of Bim reporter constructs. Expression of all six miRNAs from this cluster were elevated when Hoxb8 was overexpressed. The miR-17∼92 cluster was required for repression of Bim in Hoxb8-immortalised cells and deletion of the miR-17∼92 cluster substantially inhibited Hoxb8, but not Hoxa9, mediated survival and proliferation. Hoxb8 appears to promote miR-17∼92 expression through c-Myc, a known transcriptional regulator of the miR-17∼92 cluster. We have uncovered a previously unrecognised link between Hoxb8 expression and microRNAs that provides a new insight into the oncogenic functions of Hoxb8.
authors.affiliation: Cell signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Salmanidis
authors.forename: G
authors.initials: G
authors.lastname: Brumatti
authors.forename: N
authors.initials: N
authors.lastname: Narayan
authors.forename: B D
authors.initials: BD
authors.lastname: Green
authors.forename: J A
authors.initials: JA
authors.lastname: van den Bergen
authors.forename: J J
authors.initials: JJ
authors.lastname: Sandow
authors.forename: A G
authors.initials: AG
authors.lastname: Bert
authors.forename: N
authors.initials: N
authors.lastname: Silke
authors.forename: R
authors.initials: R
authors.lastname: Sladic
authors.forename: H
authors.initials: H
authors.lastname: Puthalakath
authors.forename: L
authors.initials: L
authors.lastname: Rohrbeck
authors.forename: T
authors.initials: T
authors.lastname: Okamoto
authors.forename: P
authors.initials: P
authors.lastname: Bouillet
authors.forename: M J
authors.initials: MJ
authors.lastname: Herold
authors.forename: G J
authors.initials: GJ
authors.lastname: Goodall
authors.forename: A M
authors.initials: AM
authors.lastname: Jabbour
authors.forename: P G
authors.initials: PG
authors.lastname: Ekert
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D016923:Cell Death / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D051017:Apoptosis Regulatory Proteins; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D018398:Homeodomain Proteins; C095822:Hoxb8 protein, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein