Hoxb8 regulates expression of microRNAs to control cell death and differentiation

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dc.contributor.authorSalmanidis, M.
dc.contributor.authorBrumatti, G.
dc.contributor.authorNarayan, N.
dc.contributor.authorGreen, B.
dc.contributor.authorvan den Bergen, J.
dc.contributor.authorSandow, J.
dc.contributor.authorBert, A.
dc.contributor.authorSilke, N.
dc.contributor.authorSladic, R.
dc.contributor.authorPuthalakath, H.
dc.contributor.authorRohrbeck, L.
dc.contributor.authorOkamoto, T.
dc.contributor.authorBouillet, P.
dc.contributor.authorHerold, M.
dc.contributor.authorGoodall, G.
dc.contributor.authorJabbour, A.
dc.contributor.authorEkert, P.
dc.date.issued2013
dc.description.abstractHoxb8 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.
dc.description.statementofresponsibilityM Salmanidis, G Brumatti, N Narayan, B D Green, J A van den Bergen, J J Sandow, A G Bert, N Silke, R Sladic, H Puthalakath, L Rohrbeck, T Okamoto, P Bouillet, M J Herold, G J Goodall, A M Jabbour, and P G Ekert
dc.identifier.citationCell Death and Differentiation, 2013; 20(10):1370-1380
dc.identifier.doi10.1038/cdd.2013.92
dc.identifier.issn1350-9047
dc.identifier.issn1476-5403
dc.identifier.orcidGoodall, G. [0000-0003-1294-0692]
dc.identifier.urihttp://hdl.handle.net/2440/81313
dc.language.isoen
dc.publisherNature Publishing Group
dc.relation.grantNHMRC
dc.rights© 2013 Macmillan Publishers Limited All rights reserved
dc.source.urihttps://doi.org/10.1038/cdd.2013.92
dc.subjectApoptosis
dc.subjectHoxb8
dc.subjectinterleukin-3
dc.subjectmicroRNA
dc.titleHoxb8 regulates expression of microRNAs to control cell death and differentiation
dc.typeJournal article
pubs.publication-statusPublished

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