Article abstract
Nature Cell Biology 10, 788 - 801 (2008)
Published online: 22 June 2008 | doi:10.1038/ncb1741
A three-step pathway comprising PLZF/miR-146a/CXCR4 controls megakaryopoiesis
Catherine Labbaye1, Isabella Spinello1, Maria Teresa Quaranta1, Elvira Pelosi1, Luca Pasquini1, Eleonora Petrucci1, Mauro Biffoni1, Eugenia Rosa Nuzzolo1, Monia Billi4, Robin Foà2, Ercole Brunetti3, Francesco Grignani4, Ugo Testa1 & Cesare Peschle1,5
Abstract
MicroRNAs (miRNAs or miRs) regulate diverse normal and abnormal cell functions. We have identified a regulatory pathway in normal megakaryopoiesis, involving the PLZF transcription factor, miR-146a and the SDF-1 receptor CXCR4. In leukaemic cell lines PLZF overexpression downmodulated miR-146a and upregulated CXCR4 protein, whereas PLZF knockdown induced the opposite effects. In vitro assays showed that PLZF interacts with and inhibits the miR-146a promoter, and that miR-146a targets CXCR4 mRNA, impeding its translation. In megakaryopoietic cultures of CD34+ progenitors, PLZF was upregulated, whereas miR-146a expression decreased and CXCR4 protein increased. MiR-146a overexpression and PLZF or CXCR4 silencing impaired megakaryocytic (Mk) proliferation, differentiation and maturation, as well as Mk colony formation. Mir-146a knockdown induced the opposite effects. Rescue experiments indicated that the effects of PLZF and miR-146a are mediated by miR-146a and CXCR4, respectively. Our data indicate that megakaryopoiesis is controlled by a cascade pathway, in which PLZF suppresses miR-146a transcription and thereby activates CXCR4 translation.
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
- Department of Cellular Biotechnologies and Hematology, Division of Hematology, 'La Sapienza' University, 00161 Rome, Italy.
- San Pietro FBF Centro Ricerche AFaR, 00100 Rome, Italy.
- Department of General Pathology, University of Perugia, 06122 Perugia, Italy.
- IRCCS MultiMedica, 20138 Milan, Italy.
Correspondence to: Catherine Labbaye1 e-mail: catherine.labbaye@iss.it
Correspondence to: Cesare Peschle1,5 e-mail: cesare.peschle@iss.it
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
RESEARCH
PLZF-mediated control on c-kit expression in CD34 + cells and early erythropoiesisOncogene Original Article
MicroRNAs 17-5p?20a?106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulationNature Cell Biology Article (01 Jul 2007)
PLZF-mediated control on VLA-4 expression in normal and leukemic myeloid cellsOncogene Original Article
MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemiaOncogene Original Article
A skin microRNA promotes differentiation by repressing ?stemness?Nature Letters to Editor (13 Mar 2008)
See all 9 matches for Research
