SIRT2 regulates ciliogenesis and contributes to abnormal centrosome amplification caused by loss of polycystin-1. Hum Mol Genet 2014 Mar 15;23(6):1644-55
Date
11/10/2013Pubmed ID
24203696Pubmed Central ID
PMC3929098DOI
10.1093/hmg/ddt556Scopus ID
2-s2.0-84894366738 (requires institutional sign-in at Scopus site) 46 CitationsAbstract
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.
Author List
Zhou X, Fan LX, Li K, Ramchandran R, Calvet JP, Li XAuthors
Keguo Li MD, PhD Research Scientist I in the Surgery department at Medical College of WisconsinRamani Ramchandran PhD Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsCell Line
Centrosome
Cilia
Gene Amplification
Gene Expression Regulation
Gene Knockdown Techniques
HEK293 Cells
Humans
Kidney
Mice
Niacinamide
Sirtuin 2
TRPP Cation Channels
Zebrafish
