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Molecular and Cellular Biology, April 2009, p. 2230-2242, Vol. 29, No. 8
0270-7306/09/$08.00+0 doi:10.1128/MCB.00743-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
E3 Ubiquitin Ligase RNF31 Cooperates with DAX-1 in Transcriptional Repression of Steroidogenesis
,
Anna Ehrlund,1
Elin Holter Anthonisen,1,2
Nina Gustafsson,1
Nicolas Venteclef,1
Kirsten Robertson Remen,1
Anastasios E. Damdimopoulos,1
Anastasia Galeeva,3,5
Markku Pelto-Huikko,3,5
Enzo Lalli,4
Knut R. Steffensen,1
Jan-Åke Gustafsson,1,6 and
Eckardt Treuter1*
Department of Biosciences and Nutrition, Karolinska Institutet, S-14157 Huddinge/Stockholm, Sweden,1 Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1046, Blindern, N-0316 Oslo, Norway,2 Department of Developmental Biology, Tampere University Medical School, FIN-33014 Tampere, Finland,3 Institut de Pharmacologie Moleculaire et Cellulaire CNRS UMR 6097 and Université de Nice Sophia Antipolis, Valbonne, France,4 Department of Pathology, Tampere University Hospital, Tampere, Finland,5 Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204-50566
Received 8 May 2008/ Returned for modification 5 June 2008/ Accepted 2 February 2009
Genetic and experimental evidence points to a critical involvement of the atypical mammalian orphan receptor DAX-1 in reproductive development and steroidogenesis. Unlike conventional nuclear receptors, DAX-1 appears not to function as a DNA-bound transcription factor. Instead, it has acquired the capability to act as a transcriptional corepressor of steroidogenic factor 1 (SF-1). The interplay of DAX-1 and SF-1 is considered a central, presumably ligand-independent element of adrenogonadal development and function that requires tight regulation. This raises a substantial interest in identifying its modulators and the regulatory signals involved. Here, we uncover molecular mechanisms that link DAX-1 to the ubiquitin modification system via functional interaction with the E3 ubiquitin ligase RNF31. We demonstrate that RNF31 is coexpressed with DAX-1 in steroidogenic tissues and participates in repressing steroidogenic gene expression. We provide evidence for the in vivo existence of a corepressor complex containing RNF31 and DAX-1 at the promoters of the StAR and CYP19 genes. Our data suggest that RNF31 functions to stabilize DAX-1, which might be linked to DAX-1 monoubiquitination. In conclusion, RNF31 appears to be required for DAX-1 to repress transcription, provides means to regulate DAX-1 in ligand-independent ways, and emerges as a relevant coregulator of steroidogenic pathways governing physiology and disease.
* Corresponding author. Mailing address: Department of Biosciences and Nutrition, Karolinska Institutet, S-14157 Huddinge/Stockholm, Sweden. Phone: 46 86089162. Fax: 46 87745538. E-mail: eckardt.treuter{at}ki.se
Published ahead of print on 23 February 2009.
Supplemental material for this article may be found at http://mcb.asm.org/.
Molecular and Cellular Biology, April 2009, p. 2230-2242, Vol. 29, No. 8
0270-7306/09/$08.00+0 doi:10.1128/MCB.00743-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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