title: MAP3K11 is a tumor suppressor targeted by the oncomiR miR-125b in early B cells.
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.
authors.affiliation: Centre for Biological Signalling Studies (bioss), Albert-Ludwigs-University Freiburg, Freiburg, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Knackmuss
authors.affiliation: Division of Developmental Immunology, Biocenter Innsbruck, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: S E
authors.initials: SE
authors.lastname: Lindner
authors.affiliation: Division of Molecular Pathophysiology, Biocenter Innsbruck, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Aneichyk
authors.affiliation: Centre for Biological Signalling Studies (bioss), Albert-Ludwigs-University Freiburg, Freiburg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Kotkamp
authors.affiliation: Centre for Biological Signalling Studies (bioss), Albert-Ludwigs-University Freiburg, Freiburg, Germany.
authors.forename: Z
authors.initials: Z
authors.lastname: Knust
authors.affiliation: Division of Developmental Immunology, Biocenter Innsbruck, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Villunger
authors.affiliation: Centre for Biological Signalling Studies (bioss), Albert-Ludwigs-University Freiburg, Freiburg, Germany.|Division of Developmental Immunology, Biocenter Innsbruck, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Herzog
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004794:Enzyme Repression; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007938:Leukemia / Q000201:enzymology / Q000235:genetics; D015448:Leukemia, B-Cell / Q000201:enzymology / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000502:physiology*; D009368:Neoplasm Transplantation; D054448:Precursor Cells, B-Lymphoid / Q000502:physiology*; D034622:RNA Interference; D025521:Tumor Suppressor Proteins / Q000502:physiology; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D020930:MAP Kinase Kinase Kinases; D035683:MicroRNAs; D025521:Tumor Suppressor Proteins; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C527468:Mirn125 microRNA, mouse