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hnRNP A1 nucleocytoplasmic shuttling activity is required for normal myelopoiesis and BCR/ABL leukemogenesis

TitolohnRNP A1 nucleocytoplasmic shuttling activity is required for normal myelopoiesis and BCR/ABL leukemogenesis
Tipo di pubblicazioneArticolo su Rivista peer-reviewed
Anno di Pubblicazione2002
AutoriIervolino, A., Santilli G., Trotta R., Guerzoni C., Cesi Vincenzo, Bergamaschi A., Gambacorti-Passerini C., Calabretta B., and Perrotti D.
RivistaMolecular and Cellular Biology
Volume22
Paginazione2255-2266
ISSN02707306
Parole chiaveanimal cell, Animalia, Animals, article, BCR ABL protein, bcr-abl, Biological Transport, bone marrow cell, cell differentiation, Cell Line, Cell Nucleus, cell proliferation, Cell Survival, Chronic, controlled study, Cultured, Cysteine Endopeptidases, cytoplasm, Eukaryota, Fusion proteins, gene expression regulation, granulocyte colony stimulating factor, Granulocytes, hematopoietic cell, heterogeneous nuclear ribonucleoprotein, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, Heterogeneous-Nuclear Ribonucleoproteins, human, human cell, Humans, Immunoblotting, interleukin 3, Leukemia, Leukemic, leukemogenesis, Leukopoiesis, Messenger, messenger RNA, messenger RNA precursor, Mice, mouse, Multienzyme Complexes, Murinae, mutation, Myeloid, Myeloid Progenitor Cells, myelopoiesis, Neoplasm, nonhuman, Northern blotting, nucleocytoplasmic transport, Phenotype, Post-Translational, priority journal, proteasome, Proteasome Endopeptidase Complex, protein bcl x, protein processing, reverse transcription polymerase chain reaction, Ribonucleoproteins, RNA, Tumor Cells, ubiquitin
Abstract

hnRNP A1 is a nucleocytoplasmic shuttling heterogeneous nuclear ribonucleoprotein that accompanies eukaryotic mRNAs from the active site of transcription to that of translation. Although the importance of hnRNP A1 as a regulator of nuclear pre-mRNA and mRNA processing and export is well established, it is unknown whether this is relevant for the control of proliferation, survival, and differentiation of normal and transformed cells. We show here that hnRNP A1 levels are increased in myeloid progenitor cells expressing the p210BCR/ABL oncoprotein, in mononuclear cells from chronic myelogenous leukemia (CML) blast crisis patients, and during disease progression. In addition, in myeloid progenitor 32Dcl3 cells, BCR/ABL stabilizes hnRNP A1 by preventing its ubiquitin/proteasome-dependent degradation. To assess the potential role of hnRNP A1 nucleocytoplasmic shuttling activity in normal and leukemic myelopoiesis, a mutant defective in nuclear export was ectopically expressed in parental and BCR/ABL-transformed myeloid precursor 32Dcl3 cells, in normal murine marrow cells, and in mononuclear cells from a CML patient in accelerated phase. In normal cells, expression of this mutant enhanced the susceptibility to apoptosis induced by interleukin-3 deprivation, suppressed granulocytic differentiation, and induced massive cell death of granulocyte colony-stimulating factor-treated cultures. In BCR/ABL-transformed cells, its expression was associated with suppression of colony formation and reduced tumorigenic potential in vivo. Moreover, interference with hnRNP A1 shuttling activity resulted in downmodulation of C/EBPα, the major regulator of granulocytic differentiation, and Bcl-XL, an important survival factor for hematopoietic cells. Together, these results suggest that the shuttling activity of hnRNP A1 is important for the nucleocytoplasmic trafficking of mRNAs that encode proteins influencing the phenotype of normal and BCR/ABL-transformed myeloid progenitors.

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URLhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-0036124398&doi=10.1128%2fMCB.22.7.2255-2266.2002&partnerID=40&md5=425bc42cb635d90ef8a7a7e65cb70982
DOI10.1128/MCB.22.7.2255-2266.2002
Citation KeyIervolino20022255