title: Inducible activation of CEBPB, a gene negatively regulated by BCR/ABL, inhibits proliferation and promotes differentiation of BCR/ABL-expressing cells.
abstract: Translational regulation by oncogenic proteins may be a rapid and efficient mechanism to modulate gene expression. We report here the identification of the CEBPB gene as a target of translational regulation in myeloid precursor cells transformed by the BCR/ABL oncogene. Expression of CEBPB was repressed in 32D-BCR/ABL cells and reinduced by imatinib (STI571) via a mechanism that appears to depend on expression of the CUG-repeat RNA-binding protein CUGBP1 and the integrity of the CUG-rich intercistronic region of c/ebpbeta mRNA. Constitutive expression or conditional activation of wild-type CEBPB induced differentiation and inhibited proliferation of 32D-BCR/ABL cells in vitro and in mice, but a DNA binding-deficient CEBPB mutant had no effect. The proliferation-inhibitory effect of CEBPB was, in part, mediated by the CEBPB-induced GADD45A gene. Because expression of CEBPB (and CEBPA) is low in the blast crisis (BC) stage of chronic myelogenous leukemia (CML) and is inversely correlated with BCR/ABL tyrosine kinase levels, these findings point to the therapeutic potential of restoring C/EBP activity in CML-BC and, perhaps, other types of acute leukemia.
authors.affiliation: Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson Medical College, 233 South and 10th Street, Philadelphia, PA 19107, USA.
authors.forename: Clara
authors.initials: C
authors.lastname: Guerzoni
authors.forename: Michela
authors.initials: M
authors.lastname: Bardini
authors.forename: Samanta A
authors.initials: SA
authors.lastname: Mariani
authors.forename: Giovanna
authors.initials: G
authors.lastname: Ferrari-Amorotti
authors.forename: Paolo
authors.initials: P
authors.lastname: Neviani
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Panno
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Robert
authors.initials: R
authors.lastname: Martinez
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
authors.forename: Bruno
authors.initials: B
authors.lastname: Calabretta
mesh_terms: D001854:Bone Marrow Cells / Q000166:cytology* / Q000502:physiology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics*; D002454:Cell Differentiation; D002478:Cells, Cultured; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D008156:Luciferases / Q000235:genetics; D016366:Open Reading Frames; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D018911:Trinucleotide Repeats
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D012333:RNA, Messenger; D008156:Luciferases; D016044:Fusion Proteins, bcr-abl