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Cell Death Differ. 2016 Feb;23(2):242-52. doi: 10.1038/cdd.2015.87. Epub 2015 Jul 3.

MAP3K11 is a tumor suppressor targeted by the oncomiR miR-125b in early B cells.

Author information

1
Centre for Biological Signalling Studies (bioss), Albert-Ludwigs-University Freiburg, Freiburg, Germany.
2
Division of Developmental Immunology, Biocenter Innsbruck, Medical University of Innsbruck, Innsbruck, Austria.
3
Division of Molecular Pathophysiology, Biocenter Innsbruck, Medical University of Innsbruck, Innsbruck, Austria.

Abstract

MicroRNAs (miRNAs) are a class of small, non-coding RNAs that posttranscriptionally regulate gene expression and thereby control most, if not all, biological processes. Aberrant miRNA expression has been linked to a variety of human diseases including cancer, but the underlying molecular mechanism often remains unclear. Here we have screened a miRNA expression library in a growth factor-dependent mouse pre-B-cell system to identify miRNAs with oncogenic activity. We show that miR-125b is sufficient to render pre-B cells growth factor independent and demonstrate that continuous expression of miR-125b is necessary to keep these cells in a transformed state. Mechanistically, we find that the expression of miR-125b protects against apoptosis induced by growth factor withdrawal, and that it blocks the differentiation of pre-B to immature B cells. In consequence, miR-125b-transformed cells maintain expression of their pre-B-cell receptor that provides signals for continuous proliferation and survival even in the absence of growth factor. Employing microarray analysis, we identified numerous targets of miR-125b, but only reconstitution of MAP3K11, a critical regulator of mitogen- and stress-activated kinase signaling, interferes with the cellular fitness of the transformed cells. Together, this indicates that MAP3K11 might function as an important tumor suppressor neutralized by oncomiR-125b in B-cell leukemia.

PMID:
26138442
PMCID:
PMC4678593
DOI:
10.1038/cdd.2015.87
[Indexed for MEDLINE]
Free PMC Article

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