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

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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 - Feb 1 2013

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Steroidogenic Factor 1
DNA-Activated Protein Kinase
Centrosome
Homeostasis
Cyclin-Dependent Kinase 2
Cyclin A
DNA Damage
DNA
Catalytic DNA
Centrioles
Cytoplasmic and Nuclear Receptors
Knockout Mice
Cell Differentiation
Catalytic Domain
Cell Survival
Apoptosis

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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Steroidogenic factor 1 (NR5A1) maintains centrosome homeostasis in steroidogenic cells by restricting centrosomal DNA-dependent protein kinase activation. / Wang, Chia Yih; Kao, Yung Hsin; Lai, Pao Yen; Chen, Wei Yi; Chung, Bon Chu.

In: Molecular and cellular biology, Vol. 33, No. 3, 01.02.2013, p. 476-484.

Research output: Contribution to journalArticle

Wang, Chia Yih ; Kao, Yung Hsin ; Lai, Pao Yen ; Chen, Wei Yi ; Chung, Bon Chu. / Steroidogenic factor 1 (NR5A1) maintains centrosome homeostasis in steroidogenic cells by restricting centrosomal DNA-dependent protein kinase activation. In: Molecular and cellular biology. 2013 ; Vol. 33, No. 3. pp. 476-484.
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