Musashi mediates translational repression of the Drosophila hypoxia inducible factor

BERTOLIN AP; KATZ MJ; YANO M; POZZI B; ACEVEDO JM; BLANCO-OBREGÓN D; GÁNDARA L; SORIANELLO E; KANDA H; OKANO H; SREBROW A; WAPPNER P

NUCLEIC ACIDS RESEARCH

OXFORD UNIV PRESS

Lugar: Oxford; Año: 2016

0305-1048

Cellular and systemic responses to low oxygen levels are principally mediated by HypoxiaInducible Factors (HIFs), a family of evolutionary conserved heterodimeric transcription factors,whose alpha- and beta-subunits belong to the bHLH-PAS family. In normoxia, HIFα ishydroxylated by specific prolyl-4-hydroxylases, targeting it for proteasomal degradation,while in hypoxia the activity of these hydroxylases decreases due to low oxygen availability,leading to HIFα accumulation and expression of HIF target genes. To identify microRNAsrequired for maximal HIF activity, we conducted an overexpression screen in Drosophilamelanogaster, evaluating the induction of a HIF transcriptional reporter. miR-190 overexpressionenhanced HIF-dependent biological responses, including terminal sprouting of thetracheal system, while in miR-190 loss of function embryos the hypoxic response wasimpaired. In hypoxic conditions, miR-190 expression was upregulated and required forinduction of HIF target genes by directly inhibiting the HIF prolyl-4-hydroxylase Fatiga.Thus, miR-190 is a novel regulator of the hypoxia response that represses the oxygen sensorFatiga, leading to HIFα stabilization and enhancement of hypoxic responses