Abstract
SF-1 (Steroidogenic Factor 1, NR5A1) is a tissue-specific transcription factor critical for the growth, development and differentiation of steroidogenic and a few other endocrine tissues. But how SF-1 regulates cell growth is not entirely clear. Here we found that SF-1 was localized to the centrosome in addition to the nucleus, and SF-1 depletion by shRNA caused centrosome over-duplication, aberrant mitosis and genomic instability, leading to a reduction of cell number. Centrosome amplification defect was rescued by both wild-type SF-1 and transcription-defective SF-1-G35E, suggesting a non-genomic activity of SF-1 involved in centrosome homeostasis. In addition, we identified in SF-1 a centrosome localization signal, whose overexpression led to reduced localization of both SF-1 and γ-tubulin to the centrosome. Our results uncover a novel role of SF-1 in the control of centrosome homeostasis and genomic stability.
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Abbreviations
- BrdU:
-
bromodeoxyuridine
- SF-1:
-
Steroidogenic Factor 1
- PCM:
-
pericentriolar material
- CLS:
-
centrosome localization signal
- HU:
-
hydroxyurea
- γ-tub:
-
γ-tubulin
References
Val P, Lefrancois-Martinez AM, Veyssiere G, Martinez A . SF-1 a key player in the development and differentiation of steroidogenic tissues. Nucl Recept 2003; 1: 8.
Little TH, Zhang Y, Matulis CK, Weck J, Zhang Z, Ramachandran A et al. Sequence-specific deoxyribonucleic acid (DNA) recognition by steroidogenic factor 1: a helix at the carboxy terminus of the DNA binding domain is necessary for complex stability. Mol Endocrinol 2006; 20: 831–843.
Parker KL, Rice DA, Lala DS, Ikeda Y, Luo X, Wong M et al. Steroidogenic factor 1: an essential mediator of endocrine development. Recent Prog Horm Res 2002; 57: 19–36.
Sadovsky Y, Dorn C . Function of steroidogenic factor 1 during development and differentiation of the reproductive system. Rev Reprod 2000; 5: 136–142.
Luo X, Ikeda Y, Parker KL . A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 1994; 77: 481–490.
Beuschlein F, Mutch C, Bavers DL, Ulrich-Lai YM, Engeland WC, Keegan C et al. Steroidogenic factor-1 is essential for compensatory adrenal growth following unilateral adrenalectomy. Endocrinology 2002; 143: 3122–3135.
Lin L, Achermann JC . Steroidogenic factor-1 (SF-1, Ad4BP, NR5A1) and disorders of testis development. Sex Dev 2008; 2: 200–209.
Doghman M, Karpova T, Rodrigues GA, Arhatte M, De Moura J, Cavalli LR et al. Increased steroidogenic factor-1 dosage triggers adrenocortical cell proliferation and cancer. Mol Endocrinol 2007; 21: 2968–2987.
Figueiredo BC, Cavalli LR, Pianovski MA, Lalli E, Sandrini R, Ribeiro RC et al. Amplification of the steroidogenic factor 1 gene in childhood adrenocortical tumors. J Clin Endocrinol Metab 2005; 90: 615–619.
Doghman M, Cazareth J, Douguet D, Madoux F, Hodder P, Lalli E et al. Inhibition of adrenocortical carcinoma cell proliferation by steroidogenic factor-1 inverse agonists. J Clin Endocrinol Metab 2009; 94: 2178–2183.
Doxsey S . Re-evaluating centrosome function. Nat Rev Mol Cell Biol 2001; 2: 688–698.
Doxsey S, Zimmerman W, Mikule K . Centrosome control of the cell cycle. Trends Cell Biol 2005; 15: 303–311.
Fukasawa K . Oncogenes and tumour suppressors take on centrosomes. Nat Rev Cancer 2007; 7: 911–924.
Nigg EA . Centrosome duplication: of rules and licenses. Trends Cell Biol 2007; 17: 215–221.
D’Assoro AB, Lingle WL, Salisbury JL . Centrosome amplification and the development of cancer. Oncogene 2002; 21: 6146–6153.
Ganem NJ, Godinho SA, Pellman D . A mechanism linking extra centrosomes to chromosomal instability. Nature 2009; 460: 278–282.
Guarguaglini G, Duncan PI, Stierhof YD, Holmstrom T, Duensing S, Nigg EA et al. The forkhead-associated domain protein Cep170 interacts with Polo-like kinase 1 and serves as a marker for mature centrioles. Mol Biol Cell 2005; 16: 1095–1107.
Meraldi P, Lukas J, Fry AM, Bartek J, Nigg EA . Centrosome duplication in mammalian somatic cells requires E2F and Cdk2-cyclin A. Nat Cell Biol 1999; 1: 88–93.
Achermann JC, Ito M, Ito M, Hindmarsh PC, Jameson JL . A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet 1999; 22: 125–126.
Nigg EA . Centrosome aberrations: cause or consequence of cancer progression? Nat Rev Cancer 2002; 2: 815–825.
Shang ZF, Huang B, Xu QZ, Zhang SM, Fan R, Liu XD et al. Inactivation of DNA-dependent protein kinase leads to spindle disruption and mitotic catastrophe with attenuated checkpoint protein 2 phosphorylation in response to DNA damage. Cancer Res 2010; 70: 3657–3666.
Rudnicki MA, Schnegelsberg PN, Stead RH, Braun T, Arnold HH, Jaenisch R . MyoD or Myf-5 is required for the formation of skeletal muscle. Cell 1993; 75: 1351–1359.
Suwabe N, Takahashi S, Nakano T, Yamamoto M . GATA-1 regulates growth and differentiation of definitive erythroid lineage cells during in vitro ES cell differentiation. Blood 1998; 92: 4108–4118.
Ito M, Achermann JC, Jameson JL . A naturally occurring steroidogenic factor-1 mutation exhibits differential binding and activation of target genes. J Biol Chem 2000; 275: 31708–31714.
Cunha-Ferreira I, Bento I, Bettencourt-Dias M . From zero to many: control of centriole number in development and disease. Traffic 2009; 10: 482–498.
Durcan TM, Halpin ES, Casaletti L, Vaughan KT, Pierson MR, Woods S et al. Centrosome duplication proceeds during mimosine-induced G1 cell cycle arrest. J Cell Physiol 2008; 215: 182–191.
Keryer G, Witczak O, Delouvee A, Kemmner WA, Rouillard D, Tasken K et al. Dissociating the centrosomal matrix protein AKAP450 from centrioles impairs centriole duplication and cell cycle progression. Mol Biol Cell 2003; 14: 2436–2446.
Gillingham AK, Munro S . The PACT domain, a conserved centrosomal targeting motif in the coiled-coil proteins AKAP450 and pericentrin. EMBO Rep 2000; 1: 524–529.
Pascreau G, Eckerdt F, Churchill ME, Maller JL . Discovery of a distinct domain in cyclin A sufficient for centrosomal localization independently of Cdk binding. Proc Natl Acad Sci USA 2010; 107: 2932–2937.
Matsumoto Y, Maller JL . A centrosomal localization signal in cyclin E required for Cdk2-independent S phase entry. Science 2004; 306: 885–888.
Raynaud-Messina B, Merdes A . Gamma-tubulin complexes and microtubule organization. Curr Opin Cell Biol 2007; 19: 24–30.
Bornens M, Paintrand M, Berges J, Marty MC, Karsenti E . Structural and chemical characterization of isolated centrosomes. Cell Motil Cytoskeleton 1987; 8: 238–249.
Acknowledgements
We thank Jeffrey L Salisbury and Chung Wang for the anti-centrin (20H5) and Hsp70 antibodies, respectively. RNAi reagents were obtained from the National RNAi Core Facility (Institute of Molecular Biology/Genomic Research Center, Academia Sinica, supported by National Research Program for Genomic Medicine, NSC 97-3112-B-001-016). This work was supported by grants from Academia Sinica and from National Science Council (NSC 97-2321-B-001-023), Taiwan.
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Lai, PY., Wang, CY., Chen, WY. et al. Steroidogenic Factor 1 (NR5A1) resides in centrosomes and maintains genomic stability by controlling centrosome homeostasis. Cell Death Differ 18, 1836–1844 (2011). https://doi.org/10.1038/cdd.2011.54
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DOI: https://doi.org/10.1038/cdd.2011.54
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