MicroRNA-340-mediated degradation of microphthalmia-associated transcription factor mRNA is inhibited by the coding region determinant-binding protein.
Alternative cleavage and polyadenylation generate multiple transcript variants of mRNA isoforms with different length of 3'-untranslated region (UTR). Alternative cleavage and polyadenylation enable differential post-transcriptional regulation of transcripts via the availability of different cis-acting elements in 3'-UTRs. Microphthalmia-associated transcription factor (MITF) is a master regulator of melanocyte development and melanogenesis. It has also been implicated in melanoma development. Here we show that melanoma cells favor the expression of MITF mRNA with shorter 3'-UTR. This isoform of mRNA is regulated by microRNA, miR-340. miR-340 interacts with two of its target sites on the 3'-UTR of MITF mRNA, causing mRNA degradation and decreased expression and activity of MITF. On the other hand, the RNA-binding protein coding region determinant-binding protein, shown to be highly expressed in melanoma, directly binds to the 3'-UTR of MITF mRNA and prevents the binding of miR-340 to its target sites, resulting in stabilization of the MITF transcript and elevated expression and transcriptional activity of MITF. This interplay between RNA-binding protein and miRNA describes the important mechanism of regulation of MITF in melanocytes and malignant melanomas.
Goswami
Srikanta
S
Department of Dermatology and the Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA.
Tarapore
Rohinton S
RS
Teslaa
Jessica J
JJ
Grinblat
Yevgenya
Y
Setaluri
Vijayasaradhi
V
Spiegelman
Vladimir S
VS
D020413:3' Untranslated Regions / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D005784:Gene Amplification; D017930:Genes, Reporter; D014644:Genetic Variation; D006801:Humans; D007700:Kinetics; D008544:Melanocytes / Q000502:physiology; D008545:Melanoma / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics; D014158:Transcription, Genetic
D020413:3' Untranslated Regions; D017931:DNA Primers; D018076:DNA, Complementary; D035683:MicroRNAs; D051739:Microphthalmia-Associated Transcription Factor; D012333:RNA, Messenger; D012334:RNA, Neoplasm