title: NR5A1 prevents centriole splitting by inhibiting centrosomal DNA-PK activation and β-catenin accumulation.
abstract: BACKGROUND
  Adrenogonadal cell growth and differentiation are controlled by nuclear receptor NR5A1 (Ad4BP/SF-1) that regulates the expression of adrenal and gonadal genes. In addition, SF-1 also resides in the centrosome and controls centrosome homeostasis by restricting the activity of centrosomal DNA-PK and CDK2/cyclin A.
  
  
  RESULTS
  Here we show that SF-1 depletion resulted in centriole splitting and amplification due to aberrant activation of DNA-PK in the centrosome of mouse adrenocortical Y1 cells. In the absence of SF-1, GSK3β was aberrantly phosphorylated during G1 phase and β-catenin was accumulated in the centrosome, but not in the nucleus. DNA-PK inhibitor vanillin reversed these phenomena. SF-1 overexpression led to inhibition of centrosomal DNA-PK activation caused by SF-1 depletion. Both full-length SF-1 and truncated SF-1 devoid of its DNA-binding domain rescued the multiple centrosome phenotype caused by SF-1 depletion, indicating that the effect of SF-1 in the centrosome is not contributed by its DNA-binding domain. Furthermore, SF-1 interacted with cyclin A in the centrosome, but not in the nucleus. Depletion of SF-1 also resulted in centriole splitting, genomic instability and reduced growth of mouse testicular Leydig MA10 cells.
  
  
  CONCLUSIONS
  Centrosomal DNA-PK signaling triggers the accumulation of β-catenin, leading to centrosome over-duplication and centriole splitting. This cascade of centrosomal events results in genomic instability and reduced cell numbers.
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, 115, Taiwan. b89609046@gmail.com.|Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan. b89609046@gmail.com.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan. b89609046@gmail.com.
authors.forename: Chia-Yih
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, 115, Taiwan. b891635@life.nthu.edu.tw.
authors.forename: Pao-Yen
authors.initials: PY
authors.lastname: Lai
authors.affiliation: Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan. qooq118@hotmail.com.
authors.forename: Ting-Yu
authors.initials: TY
authors.lastname: Chen
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, 115, Taiwan. mbchung@sinica.edu.tw.
authors.forename: Bon-Chu
authors.initials: BC
authors.lastname: Chung
mesh_terms: D000818:Animals; D002460:Cell Line; D018385:Centrosome / Q000378:metabolism*; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D054339:Steroidogenic Factor 1 / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D054339:Steroidogenic Factor 1; D051176:beta Catenin; D051747:DNA-Activated Protein Kinase