c-Myb oncoprotein is an essential target of the dleu2 tumor suppressor microRNA cluster.
The dleu2 tumor suppressor locus encodes two microRNAs, miR-15a and miR-16, which are thought to play an important role in B-cell neoplasms. However, relatively little is known about proteins that regulate or are regulated by this microRNA cluster. Here we demonstrate that the Pax5 oncoprotein downregulates the dleu2 gene and at the same time boosts expression of its own heterodimeric partner c-Myb. Interestingly, c-Myb upregulation occurs primarily at a post-transcriptional level, suggesting that it might be a target for microRNAs such as miR-15a/16. Indeed, miR-15a/16 have predicted binding sites in the c-Myb 3'-UTR and through them diminish protein output in luciferase sensor assays. Moreover, forced overexpression of miR-15a/16 reduces endogenous c-Myb levels and compromises Pax5 function. Conversely, restoration of c-Myb levels partly alleviates tumors suppressive effects of miR-15a/16, suggesting that c-Myb is a key downstream target of this microRNA cluster.
Chung
Elaine Y
EY
Department of Pathobiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Dews
Michael
M
Cozma
Diana
D
Yu
Duonan
D
Wentzel
Erik A
EA
Chang
Tsung-Cheng
TC
Schelter
Janell M
JM
Cleary
Michele A
MA
Mendell
Joshua T
JT
Thomas-Tikhonenko
Andrei
A
D020413:3' Untranslated Regions; D001483:Base Sequence; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D051757:PAX5 Transcription Factor / Q000378:metabolism*; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D062085:RNA, Long Noncoding; D014166:Transferases; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D020413:3' Untranslated Regions; C109420:DLEU2 lncRNA, human; C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D020598:Proto-Oncogene Proteins c-myb; D062085:RNA, Long Noncoding; D025521:Tumor Suppressor Proteins; D014166:Transferases