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Mol. Cell. Biol. 33 (3): 476-484

Copyright © 2013 by the American Society for Microbiology. All rights reserved.

Steroidogenic Factor 1 (NR5A1) Maintains Centrosome Homeostasis in Steroidogenic Cells by Restricting Centrosomal DNA-Dependent Protein Kinase Activation

Chia-Yih Wang,a Yung-Hsin Kao,a,b Pao-Yen Lai,a Wei-Yi Chen,a,*, and Bon-chu Chunga

Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan,a Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, Taipei, Taiwan,b

Received for publication 3 August 2012. Revision received 2 September 2012. Accepted for publication 5 November 2012.

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.


Address correspondence to Bon-chu Chung, mbchung{at}sinica.edu.tw.

* Present address: Wei-Yi Chen, Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York, USA.

Published ahead of print 19 November 2012

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01064-12.



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