Extensive post-transcriptional regulation of microRNAs and its implications for cancer.
MicroRNAs (miRNAs) are short, noncoding RNAs that post-transcriptionally regulate gene expression. While hundreds of mammalian miRNA genes have been identified, little is known about the pathways that regulate the production of active miRNA species. Here we show that a large fraction of miRNA genes are regulated post-transcriptionally. During early mouse development, many miRNA primary transcripts, including the Let-7 family, are present at high levels but are not processed by the enzyme Drosha. An analysis of gene expression in primary tumors indicates that the widespread down-regulation of miRNAs observed in cancer is due to a failure at the Drosha processing step. These data uncover a novel regulatory step in miRNA function and provide a mechanism for miRNA down-regulation in cancer.
Thomson
J Michael
JM
Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Newman
Martin
M
Parker
Joel S
JS
Morin-Kensicki
Elizabeth M
EM
Wright
Tricia
T
Hammond
Scott M
SM
D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000378:metabolism*; D047108:Embryonic Development; D005260:Female; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012323:RNA Processing, Post-Transcriptional; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D018243:Teratocarcinoma / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D035683:MicroRNAs; C513400:Drosha protein, mouse; D043244:Ribonuclease III