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Molecular and Cellular Biology, July 2008, p. 4394-4406, Vol. 28, No. 13
0270-7306/08/$08.00+0     doi:10.1128/MCB.01914-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Downregulation of Vertebrate Tel (ETV6) and Drosophila Yan Is Facilitated by an Evolutionarily Conserved Mechanism of F-Box-Mediated Ubiquitination{triangledown} ,§

M. Guy Roukens,1,{dagger} Mariam Alloul-Ramdhani,1,{dagger} Setareh Moghadasi,1 Marjolein Op den Brouw,2 and David A. Baker1*

Leiden University Medical Center (LUMC), Signaling and Transcription Laboratory, Department of Molecular Cell Biology, 2300 RC Leiden, The Netherlands,1 Laboratory of Gastroenterology and Hepatology, Erasmus University Medical Center, 2040 CA Rotterdam, The Netherlands2

Received 24 October 2007/ Returned for modification 6 February 2008/ Accepted 11 April 2008

The vertebrate Ets transcriptional repressor Tel (ETV6) and its invertebrate orthologue, Yan, are both indispensable for development, and they orchestrate cell growth and differentiation by binding to DNA, thus inhibiting gene expression. To trigger cell differentiation, these barriers to transcriptional activation must be relieved, and it is established that posttranslational modifications, such as phosphorylation and sumoylation, can specifically impair the repressive functions of Tel and Yan and are crucial for modulating their transcriptional activity. To date, however, relatively little is known about the control of Tel and Yan protein degradation. In recent years, there has been a concentrated effort to assign functions to the large number of F-box proteins encoded by both vertebrate and invertebrate genomes. Here, we report the identification and characterization of a previously unreported, evolutionarily conserved F-box protein named Fbl6. We isolated both human and Drosophila melanogaster fbl6 cDNA and show that the encoded Fbl6 protein binds to both Tel and Yan via their SAM domains. We demonstrate that both Tel and Yan are ubiquitinated, a process which is stimulated by Fbl6 and leads to proteasomal degradation. We recently established that the sumoylation of Tel on lysine 11 negatively regulates its repressive function and that the sumoylation of Tel monomers, but not that of Tel oligomers, may sensitize Tel for proteasomal degradation. Here, we found that Fbl6 regulates Tel/Yan protein stability and allows appropriate spatiotemporal control of gene expression by these repressors.

* Corresponding author. Mailing address: Leiden University Medical Center (LUMC), Department of Molecular Cell Biology, 2300 RC Leiden, The Netherlands. Phone: 31 71 526 9223. Fax: 31 71 526 8270. E-mail: d.baker{at}lumc.nl

{triangledown} Published ahead of print on 21 April 2008.

§ Supplemental material for this article may be found at http://mcb.asm.org/.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, July 2008, p. 4394-4406, Vol. 28, No. 13
0270-7306/08/$08.00+0     doi:10.1128/MCB.01914-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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