Steroidogenic factor 1 (NR5A1) maintains centrosome homeostasis in steroidogenic cells by restricting centrosomal DNA-dependent protein kinase activation

Chia Yih Wang, Yung Hsin Kao, Pao Yen Lai, Wei Yi Chen, Bon Chu Chung

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Steroidogenic factor 1 (SF-1 or NR5A1) is a nuclear receptor that controls adrenogenital cell growth and differentiation. Adrenogenital primordial cells from SF-1 knockout mice die of apoptosis, but the mechanism by which SF-1 regulates cell survival is not entirely clear. Besides functioning in the nucleus, SF-1 also resides in the centrosome and controls centrosome homeostasis. Here, we show that SF-1 restricts centrosome overduplication by inhibiting aberrant activation of DNA-dependent protein kinase (DNA-PK) in the centrosome. SF-1 was found to be associated with Ku70/Ku80 only in the centrosome, sequestering them from the catalytic subunit of DNA-PK (DNA-PKcs). In the absence of SF-1, DNA-PKcs was recruited to the centrosome and activated, causing aberrant activation of centrosomal Akt and cyclin-dependent kinase 2 (CDK2)/cyclin A and leading to centrosome overduplication. Centrosome overduplication caused by SF-1 depletion was averted by the elimination of DNA-PKcs, Ku70/80, or cyclin A or by the inhibition of CDK2 or Akt. In the nucleus, SF-1 did not interact with Ku70/80, and SF-1 depletion did not activate a nuclear DNA damage response. Centriole biogenesis was also unaffected. Thus, centrosomal DNA-PK signaling triggers centrosome overduplication, and this centrosomal event, but not the nuclear DNA damage response, is controlled by SF-1.

Original languageEnglish
Pages (from-to)476-484
Number of pages9
JournalMolecular and Cellular Biology
Volume33
Issue number3
DOIs
Publication statusPublished - 2013 Feb 1

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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