Constitutive Dicer1 phosphorylation accelerates metabolism and aging in vivo.
Proc Natl Acad Sci U S A
; 116(3): 960-969, 2019 01 15.
Article
em En
| MEDLINE
| ID: mdl-30593561
ABSTRACT
DICER1 gene alterations and decreased expression are associated with developmental disorders and diseases in humans. Oscillation of Dicer1 phosphorylation and dephosphorylation regulates its function during the oocyte-to-embryo transition in Caenorhabditis elegans Dicer1 is also phosphorylated upon FGF stimulation at conserved serines in mouse embryonic fibroblasts and HEK293 cells. However, whether phosphorylation of Dicer1 has a role in mammalian development remains unknown. To investigate the consequence of constitutive phosphorylation, we generated phosphomimetic knock-in mouse models by replacing conserved serines 1712 and 1836 with aspartic acids individually or together. Dicer1S1836D/S1836D mice display highly penetrant postnatal lethality, and the few survivors display accelerated aging and infertility. Homozygous dual-phosphomimetic Dicer1 augments these defects, alters metabolism-associated miRNAs, and causes a hypermetabolic phenotype. Thus, constitutive phosphorylation of Dicer1 results in multiple pathologic processes in mice, indicating that phosphorylation tightly regulates Dicer1 function and activity in mammals.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Envelhecimento
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Mutação de Sentido Incorreto
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Ribonuclease III
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RNA Helicases DEAD-box
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Homozigoto
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article