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Mol. Cell. Biol. doi:10.1128/MCB.01914-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Down regulation of vertebrate Tel (ETV6) and Drosophila Yan is facilitated by an evolutionarily conserved mechanism of F-box-mediated ubiquitination

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

^* To whom correspondence should be addressed. Email: d.baker{at}lumc.nl.

	Abstract

The vertebrate Ets transcriptional repressor Tel (ETV6), and its invertebrate orthologue Yan, are each indispensable for development, and orchestrate cell growth and differentiation by binding to DNA thus inhibiting gene expression. To trigger cell differentiation this barrier to transcriptional activation must be relieved and it is established that post-translational modifications such as phosphorylation and sumoylation can specifically impair their repressive function 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 numbers 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 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, which is stimulated by Fbl6, and leads to their proteasomal degradation. We recently established that sumoylation of Tel lysine 11 negatively regulates its repressive function and that sumoylation of Tel monomers but not Tel oligomers may sensitize Tel for proteasomal degradation. Here we found that Fbl6 regulates Tel/Yan protein stability and allows appropriate spatio-temporal control of gene expression by these repressors.