Ectopic over-expression of tristetraprolin in human cancer cells promotes biogenesis of let-7 by down-regulation of Lin28.
Tristetraprolin (TTP) is a AU-rich element (ARE) binding protein and exhibits suppressive effects on cell growth through down-regulation of ARE-containing oncogenes. The let-7 microRNA has emerged as a significant factor in tumor suppression. Both TTP and let-7 are often repressed in human cancers, thereby promoting oncogenesis by derepressing their target genes. In this work, an unexpected link between TTP and let-7 has been found in human cancer cells. TTP promotes an increase in expression of mature let-7, which leads to the inhibition of let-7 target gene CDC34 expression and suppresses cell growth. This event is associated with TTP-mediated inhibition of Lin28, which has emerged as a negative modulator of let-7. Lin28 mRNA contains ARE within its 3'-UTR and TTP enhances the decay of Lin28 mRNA through binding to its 3'-UTR. This suggests that the TTP-mediated down-regulation of Lin28 plays a key role in let-7 miRNA biogenesis in cancer cells.
Department of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea.
Chae Won
CW
Kim
Mai-Tram
MT
Vo
Hong Kyeung
HK
Kim
Hyun Hee
HH
Lee
Nal Ae
NA
Yoon
Byung Ju
BJ
Lee
Young Joo
YJ
Min
Won Duk
WD
Joo
Hee Jeong
HJ
Cha
Jeong Woo
JW
Park
Wha Ja
WJ
Cho
D020413:3' Untranslated Regions; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D064173:Anaphase-Promoting Complex-Cyclosome; D048708:Cell Growth Processes; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D051816:Tristetraprolin / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism
D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; C516326:LIN28B protein, human; D035683:MicroRNAs; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051816:Tristetraprolin; C487931:mirnlet7 microRNA, human; C577447:CDC34 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome