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Human Molecular Genetics Advance Access originally published online on May 26, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 14 1505-1514
DOI: 10.1093/hmg/ddh163
Human Molecular Genetics, Vol. 13, No. 14 © Oxford University Press 2004; all rights reserved

The subcellular localization of the ChoRE-binding protein, encoded by the Williams–Beuren syndrome critical region gene 14, is regulated by 14-3-3

Giuseppe Merla{dagger}, Cédric Howald, Stylianos E. Antonarakis and Alexandre Reymond*,{ddagger}

Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland

Received March 22, 2004; Accepted May 13, 2004

The Williams–Beuren syndrome (WBS) is a contiguous gene syndrome caused by chromosomal rearrangements at chromosome band 7q11.23. Several endocrine phenotypes, in particular impaired glucose tolerance and silent diabetes, have been described for this clinically complex disorder. The WBSCR14 gene, one of the genes mapping to the WBS critical region, encodes a member of the basic-helix-loop-helix leucine zipper family of transcription factors, which dimerizes with the Max-like protein, Mlx. This heterodimeric complex binds and activates, in a glucose-dependent manner, carbohydrate response element (ChoRE) motifs in the promoter of lipogenic enzymes. We identified five novel WBSCR14-interacting proteins, four 14-3-3 isotypes and NIF3L1, which form a single polypeptide complex in mammalian cells. Phosphatase treatment abrogates the association between WBSCR14 and 14-3-3, as shown previously for multiple 14-3-3 interactors. WBSCR14 is exported actively from the nucleus through a CRM1-dependent mechanism. This translocation is contingent upon the ability to bind 14-3-3. Through this mechanism the 14-3-3 isotypes directly affect the WBSCR14:Mlx complexes, which activate the transcription of lipogenic genes.

* To whom correspondence should be addressed at: Department of Genetic Medicine and Development, University of Geneva Medical School, CMU, 1, rue Michel Servet, 1211 Geneva 4, Switzerland. Tel: +41 223795719; Fax: + 41 223795706; Email: alexandre.reymond{at}medecine.unige.ch


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