SIRT2 regulates ciliogenesis and contributes to abnormal centrosome amplification caused by loss of polycystin-1.
Hum Mol Genet
; 23(6): 1644-55, 2014 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-24203696
ABSTRACT
The mechanisms underlying many of the human disease phenotypes associated with ciliary dysfunction and abnormal centrosome amplification have yet to be fully elucidated. Here, we present for the first time that SIRT2, a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, regulates ciliogenesis and centrosome amplification. Overexpression of SIRT2 in renal epithelial cells appeared to disrupt cilia formation, causing decreased numbers of cells with cilia and decreased cilia length, while inhibition of SIRT2 activity by nicotinamide treatment or knockdown of SIRT2 with siRNA was shown to block cilia disassembly during the cell cycle. Overexpression of SIRT2 in zebrafish decreased cilia numbers in Kupffer's vesicle, while morpholino knock down of SIRT2 increased cilia length. Aberrant centrosome amplification and polyploidy were seen with overexpression of SIRT2 in mouse inner medullary collecting duct 3 cells, similar to that observed following Pkd1 knockdown. SIRT2 was up-regulated in both Pkd1 mutant and knockdown cells. Depletion of SIRT2 prevented the abnormal centrosome amplification and polyploidy associated with loss of polycystin-1 (PC1) alone. Thus, we conclude that the aberrant centrosome amplification and polyploidy in Pkd1 mutant or depleted cells was mediated through overexpression of SIRT2. Our results suggest a novel function of SIRT2 in cilia dynamics and centrosome function, and in ciliopathy-associated disease progression.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Cílios
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Centrossomo
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Canais de Cátion TRPP
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Sirtuína 2
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Rim
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Hum Mol Genet
Assunto da revista:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Ano de publicação:
2014
Tipo de documento:
Article