Inducible activation of CEBPB, a gene negatively regulated by BCR/ABL, inhibits proliferation and promotes differentiation of BCR/ABL-expressing cells.
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.
Guerzoni
Clara
C
Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson Medical College, 233 South and 10th Street, Philadelphia, PA 19107, USA.
Bardini
Michela
M
Mariani
Samanta A
SA
Ferrari-Amorotti
Giovanna
G
Neviani
Paolo
P
Panno
Maria Luisa
ML
Zhang
Ying
Y
Martinez
Robert
R
Perrotti
Danilo
D
Calabretta
Bruno
B
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
D022782:CCAAT-Enhancer-Binding Protein-beta; D012333:RNA, Messenger; D008156:Luciferases; D016044:Fusion Proteins, bcr-abl