title: miR-19a: an effective regulator of SOCS3 and enhancer of JAK-STAT signalling.
abstract: Suppressors of cytokine signalling (SOCS) proteins are classic inhibitors of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Many cytokines and pathogenic mediators induce expression of SOCS, which act in a negative feedback loop to inhibit further signal transduction. SOCS mRNA expression is regulated by DNA binding of STAT proteins, however, their post-transcriptional regulation is poorly understood. microRNAs (miRNAs) are small non-coding RNAs that bind to complementary sequences on target mRNAs, often silencing gene expression. miR-19a has been shown to regulate SOCS1 expression during mutiple myeloma and be induced by the anti-viral cytokine interferon-(IFN)-α, suggesting a role in the regulation of the JAK-STAT pathway. This study aimed to identify targets of miR-19a in the JAK-STAT pathway and elucidate the functional consequences. Bioinformatic analysis identified highly conserved 3'UTR miR-19a target sequences in several JAK-STAT associated genes, including SOCS1, SOCS3, SOCS5 and Cullin (Cul) 5. Functional studies revealed that miR-19a significantly decreased SOCS3 mRNA and protein, while a miR-19a antagomir specifically reversed its inhibitory effect. Furthermore, miR-19a-mediated reduction of SOCS3 enhanced IFN-α and interleukin (IL)-6 signal transduction through STAT3. These results reveal a novel mechanism by which miR-19a may augment JAK-STAT signal transduction via control of SOCS3 expression and are fundamental to the understanding of inflammatory regulation.
authors.affiliation: School of Biochemistry and Immunology, Trinity College, University of Dublin, Dublin, Ireland.
authors.forename: Aideen S
authors.initials: AS
authors.lastname: Collins
authors.forename: Claire E
authors.initials: CE
authors.lastname: McCoy
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Lloyd
authors.forename: Cliona
authors.initials: C
authors.lastname: O'Farrelly
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Stevenson
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics*
chemical_list: D016898:Interferon-alpha; D007375:Interleukin-1; C549214:MIRN19A microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C106644:SOCS3 protein, human; D050791:STAT Transcription Factors; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053612:Janus Kinases
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