The ribonuclease DIS3 promotes let-7 miRNA maturation by degrading the pluripotency factor LIN28B mRNA.
Bottom Line: DIS3 facilitates the maturation of let-7 miRNAs by reducing in the cytoplasm the RNA stability of the pluripotency factor LIN28B, a inhibitor of let-7 processing.DIS3 inactivation, through the increase of LIN28B and the reduction of mature let-7, enhances the translation of let-7 targets such as MYC and RAS leading to enhanced tumorigenesis.Our study establishes that the ribonuclease DIS3, targeting LIN28B, sustains the maturation of let-7 miRNAs and suggests the increased translation of critical oncogenes as one of the biological outcomes of DIS3 inactivation.
Affiliation: Functional Genomics of Cancer Unit, Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, 20133 Milan, Italy.Show MeSH
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Mentions: In this study, we provide evidences that DIS3 inactivation stimulates oncogenic signaling pathways through a down-regulation of the tumor suppressor miRNA family let-7. DIS3 loss selectively increases LIN28B levels, a negative regulator of let-7 maturation. The up-regulation of LIN28B decreases mature let-7 and de-represses of downstream let-7 targets. In particular the protein levels of two critical oncogenes, MYC and RAS, increased. Indeed, DIS3 knockdown transformed NIH3T3 cells (Figure 7).
Affiliation: Functional Genomics of Cancer Unit, Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, 20133 Milan, Italy.