B-cell receptor activation induces BIC/miR-155 expression through a conserved AP-1 element.
microRNA-155 is an oncogenic microRNA that has been shown to be critical for B-cell maturation and immunoglobulin production in response to antigen. In line with its function in B-cell activation, miR-155, and its primary transcript, B-cell integration cluster (BIC), is induced by B-cell receptor (BCR) cross-linking. Using pharmacological inhibitors in the human B-cell line, Ramos, we show that activation of BIC and miR-155 expression by BCR signaling occurs through the extracellular signaling-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways but not the p38 pathway. BCR activation results in the induction of c-Fos, FosB, and JunB, and expression of these are suppressed by ERK and JNK inhibitors. Reporter analysis established a key role for a conserved AP-1 site approximately 40 bp upstream from the site of initiation but not an upstream NF-kappaB site or a putative c-Ets located at the site of initiation. Lastly, chromatin immunoprecipitation analysis demonstrated the recruitment of FosB and JunB to the miR-155 promoter following BCR activation. These results identify key determinants of BCR-mediated signaling that lead to the induction of BIC/miR-155.
Department of Pathology, Tulane Health Sciences Center and Tulane Cancer Center, New Orleans, LA 70112, USA.
Qinyan
Q
Yin
Xia
X
Wang
Jane
J
McBride
Claire
C
Fewell
Erik
E
Flemington
D001402:B-Lymphocytes / Q000378:metabolism*; D001483:Base Sequence; D002460:Cell Line; D017124:Conserved Sequence; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D017931:DNA Primers; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D011947:Receptors, Antigen, B-Cell; D018808:Transcription Factor AP-1