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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.

SUBMITTER: Salmanidis M

PROVIDER: S-EPMC3770316 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Hoxb8 regulates expression of microRNAs to control cell death and differentiation.

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

Cell death and differentiation 20130719 10

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 ...[more]

PMID: 23872792

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Hoxb8 regulates expression of microRNAs to control cell death and differentiation.

Publications

Hoxb8 regulates expression of microRNAs to control cell death and differentiation.

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