Hoxb8 regulates expression of microRNAs to control cell death and differentiation
Date
2013
Authors
Salmanidis, M.
Brumatti, G.
Narayan, N.
Green, B.
van den Bergen, J.
Sandow, J.
Bert, A.
Silke, N.
Sladic, R.
Puthalakath, H.
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Journal article
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Cell Death and Differentiation, 2013; 20(10):1370-1380
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M 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
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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.
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© 2013 Macmillan Publishers Limited All rights reserved