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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.

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


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.

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