miR-451 protects against erythroid oxidant stress by repressing 14-3-3 zeta

Yu D, dos Santos CO, Zhao G, Jiang J, Amigo JD, Khandros E, Dore LC, Yao Y, D'Souza J, Zhang Z, Ghaffari S, Choi J, Friend S, Tong W, Orange JS, Paw BH, Weiss MJ.


The bicistronic microRNA (miRNA) locus miR-144/451 is highly expressed during erythrocyte development, although its physiological roles are poorly understood. We show that miR-144/451 ablation in mice causes mild erythrocyte instability and increased susceptibility to damage after exposure to oxidant drugs. This phenotype is deeply conserved, as miR-451 depletion synergizes with oxidant stress to cause profound anemia in zebrafish embryos. At least some protective activities of miR-451 stem from its ability to directly suppress production of 14-3-3 zeta, a phospho-serine/threonine-binding protein that inhibits nuclear accumulation of transcription factor FoxO3, a positive regulator of erythroid anti-oxidant genes. Thus, in miR-144/451(-/-) erythroblasts, 14-3-3 zeta accumulates, causing partial relocalization of FoxO3 from nucleus to cytoplasm with dampening of its transcriptional program, including anti-oxidant-encoding genes Cat and Gpx1. Supporting this mechanism, overexpression of 14-3-3 zeta in erythroid cells and fibroblasts inhibits nuclear localization and activity of FoxO3. Moreover, shRNA suppression of 14-3-3 zeta protects miR-144/451(-/-) erythrocytes against peroxide-induced destruction, and restores catalase activity. Our findings define a novel miRNA-regulated pathway that protects erythrocytes against oxidant stress, and, more generally, illustrate how a miRNA can influence gene expression by altering the activity of a key transcription factor.

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Título según WOS: miR-451 protects against erythroid oxidant stress by repressing 14-3-3 zeta
Título de la Revista: GENES DEVELOPMENT
Volumen: 24
Número: 15
Fecha de publicación: 2010
Página de inicio: 1620
Página final: 1633
Idioma: English
URL: http://genesdev.cshlp.org/cgi/doi/10.1101/gad.1942110


Notas: ISI