title: MicroRNA-340-mediated degradation of microphthalmia-associated transcription factor (MITF) mRNA is inhibited by coding region determinant-binding protein (CRD-BP).
abstract: Alternative cleavage and polyadenylation generates multiple transcript variants producing mRNA isoforms with different length 3'-UTRs. Alternative cleavage and polyadenylation enables differential post-transcriptional regulation 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. This central transcription factor is also implicated in melanoma development. Here, we show that melanoma cells favor the expression of MITF mRNA with a shorter 3'-UTR. We also establish that this isoform is regulated by a micro RNA (miRNA/miR), miR-340. miR-340 interacts with two of its target sites on the MITF 3'-UTR, causing mRNA degradation as well as decreased expression and activity of MITF. Conversely, the RNA-binding protein, coding region determinant-binding protein, was 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 the stabilization of MITF transcripts, elevated expression, and transcriptional activity of MITF. This regulatory interplay between RNA-binding protein and miRNA highlights an important mechanism for the regulation of MITF in melanocytes and malignant melanomas.
authors.affiliation: From the Department of Dermatology and Paul P. Carbone Comprehensive Cancer Center.
authors.forename: Srikanta
authors.initials: S
authors.lastname: Goswami
authors.affiliation: From the Department of Dermatology and Paul P. Carbone Comprehensive Cancer Center, the Molecular and Environmental Toxicology Center, and.
authors.forename: Rohinton S
authors.initials: RS
authors.lastname: Tarapore
authors.affiliation: From the Department of Dermatology and Paul P. Carbone Comprehensive Cancer Center, the Molecular and Environmental Toxicology Center, and.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Poenitzsch Strong
authors.affiliation: the Departments of Zoology and Anatomy, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: TeSlaa
authors.affiliation: the Molecular and Environmental Toxicology Center, and the Departments of Zoology and Anatomy, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706.
authors.forename: Yevgenya
authors.initials: Y
authors.lastname: Grinblat
authors.affiliation: From the Department of Dermatology and Paul P. Carbone Comprehensive Cancer Center.
authors.forename: Vijayasaradhi
authors.initials: V
authors.lastname: Setaluri
authors.affiliation: From the Department of Dermatology and Paul P. Carbone Comprehensive Cancer Center, the Molecular and Environmental Toxicology Center, and spiegelman@dermatology.wisc.edu.
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Spiegelman
mesh_terms: D020413:3' Untranslated Regions; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008544:Melanocytes / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D020871:RNA Stability; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D020413:3' Untranslated Regions; C406144:IGF2BP1 protein, human; C570046:MIRN340 microRNA, human; C497234:MITF protein, human; D035683:MicroRNAs; D051739:Microphthalmia-Associated Transcription Factor; D020033:Protein Isoforms; D016601:RNA-Binding Proteins
keywords: Alternative Cleavage and Polyadenylation; CRD-BP; IGF2BP1; MITF; Melanogenesis; Melanoma; MicroRNA (miRNA); Ribonuclear Protein (RNP); mRNA; mRNA Decay; miRNA