Hoxb8 regulates expression of microRNAs to control cell death and differentiation

Salmanidis, M; Brumatti, G; Narayan, N; Green, BD; van den Bergen, JA; Sandow, JJ; Bert, AG; Silke, N; Sladic, R; Puthalakath, H; Rohrbeck, L; Okamoto, T; Bouillet, P; Herold, MJ; Goodall, GJ; Jabbour, AM; Ekert, PG

Author(s): Salmanidis, M; Brumatti, G; Narayan, N; Green, BD; van den Bergen, JA; Sandow, JJ; Bert, AG; Silke, N; Sladic, R; Puthalakath, H; Rohrbeck, L; Okamoto, T; Bouillet, P; Herold, MJ; Goodall, GJ; Jabbour, AM; Ekert, PG;
Details: Publication Year 2013-10,Volume 20,Issue #10,Page 1370-1380
Journal Title: CELL DEATH AND DIFFERENTIATION
Publication Type: Journal Article
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 similar to 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 similar to 92 cluster was required for repression of Bim in Hoxb8-immortalised cells and deletion of the miR-17 similar to 92 cluster substantially inhibited Hoxb8, but not Hoxa9, mediated survival and proliferation. Hoxb8 appears to promote miR-17 similar to 92 expression through c-Myc, a known transcriptional regulator of the miR-17 similar to 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.
Publisher: NATURE PUBLISHING GROUP
Keywords: Apoptosis; Hoxb8; interleukin-3; microRNA
Research Division(s): Molecular Genetics Of Cancer; Cell Signalling And Cell Death
Link To PubMed Central Version: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3770316/
Publisher's Version: https://doi.org/10.1038/cdd.2013.92

Creation Date: 2013-10-01 12:00:00