title: Altered CELF1 binding to target transcripts in malignant T cells.
abstract: The RNA-binding protein, CELF1, binds to a regulatory sequence known as the GU-rich element (GRE) and controls a network of mRNA transcripts that regulate cellular activation, proliferation, and apoptosis. We performed immunoprecipitation using an anti-CELF1 antibody, followed by identification of copurified transcripts using microarrays. We found that CELF1 is bound to a distinct set of target transcripts in the H9 and Jurkat malignant T-cell lines, compared with primary human T cells. CELF1 was not phosphorylated in resting normal T cells, but in malignant T cells, phosphorylation of CELF1 correlated with its inability to bind to GRE-containing mRNAs that served as CELF1 targets in normal T cells. Lack of binding by CELF1 to these mRNAs in malignant T cells correlated with stabilization and increased expression of these transcripts. Several of these GRE-containing transcripts that encode regulators of cell growth were also stabilized and up-regulated in primary tumor cells from patients with T-cell acute lymphoblastic leukemia. Interestingly, transcripts encoding numerous suppressors of cell proliferation that served as targets of CELF1 in malignant T cells, but not normal T cells, exhibited accelerated degradation and reduced expression in malignant compared with normal T cells, consistent with the known function of CELF1 to mediate degradation of bound transcripts. Overall, CELF1 dysfunction in malignant T cells led to the up-regulation of a subset of GRE-containing transcripts that promote cell growth and down-regulation of another subset that suppress cell growth, producing a net effect that would drive a malignant phenotype.
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA Department of Microbiology, University of Minnesota, Minneapolis, Minnesota 55455, USA Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Bohjanen
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Mai Lee
authors.initials: ML
authors.lastname: Moua
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Guo
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Ammanuel
authors.initials: A
authors.lastname: Taye
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Vlasova-St Louis
mesh_terms: D000067879:CELF1 Protein / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D000067879:CELF1 Protein; C102843:CELF1 protein, human; D012333:RNA, Messenger
keywords: CELF1 phosphorylation; GRE; GU-rich element; cancer; mRNA stability