The Role of Steroidogenic Factor 1 in Regulating Centrosome Homeostasis
Date Issued
2011
Date
2011
Author(s)
Wang, Chia-Yih
Abstract
DNA damage checkpoint proteins reside in the nucleus and the centrosome. In the nucleus, they maintain genomic integrity; however, their function in the centrosome remains unclear. Here I show that one such checkpoint protein, DNA-PK, controls centrosome duplication. In adrenocortical Y1 cells, DNA-PK activity is inhibited by SF-1 (NR5A1), which interacts with and sequesters Ku70/Ku80 from DNA-PK catalytic subunit in the centrosome. Following SF-1 depletion by shRNA, centrosomal DNA-PK was aberrantly activated, triggering centrosomal Akt (PKB) signaling, leading to accumulation of β-catenin and Cyclin A/CDK2 in the centrosome, causing centriole splitting and over-duplication. SF-1 depletion did not, however, induce DNA damage response and Akt signaling in other cellular compartments. Inhibition of DNA-PK/Akt in HeLa, U2OS, and H1299 cells also blocked centrosome over-duplication upon replication stress. I have, thus, uncovered a novel function of DNA-PK/Akt signaling in controlling centrosome duplication.
Subjects
centrosome
SF-1
DNA-PK
Akt
DNA damage
Type
thesis
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