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Molecular and Cellular Biology, November 2001, p. 7256-7267, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7256-7267.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The Transcriptional Repressor REST Determines the Cell-Specific Expression of the Human MAPK8IP1 Gene Encoding IB1 (JIP-1)

Amar Abderrahmani,1 Myriam Steinmann,1 Valérie Plaisance,1 Guy Niederhauser,1 Jacques-Antoine Haefliger,1 Vincent Mooser,1 Christophe Bonny,2 Pascal Nicod,1 and Gérard Waeber1,*

Department of Internal Medicine1 and Department of Medical Genetics,2 CHUV-University Hospital, Lausanne, Switzerland

Received 12 January 2001/Returned for modification 25 April 2001/Accepted 31 July 2001

Islet-brain 1 (IB1) is the human and rat homologue of JIP-1, a scaffold protein interacting with the c-Jun amino-terminal kinase (JNK). IB1 expression is mostly restricted to the endocrine pancreas and to the central nervous system. Herein, we explored the transcriptional mechanism responsible for this preferential islet and neuronal expression of IB1. A 731-bp fragment of the 5' regulatory region of the human MAPK8IP1 gene was isolated from a human BAC library and cloned upstream of a luciferase reporter gene. This construct drove high transcriptional activity in both insulin-secreting and neuron-like cells but not in unrelated cell lines. Sequence analysis of this promoter region revealed the presence of a neuron-restrictive silencer element (NRSE) known to bind repressor zinc finger protein REST. This factor is not expressed in insulin-secreting and neuron-like cells. By mobility shift assay, we confirmed that REST binds to the NRSE present in the IB1 promoter. Once transiently transfected in beta -cell lines, the expression vector encoding REST repressed IB1 transcriptional activity. The introduction of a mutated NRSE in the 5' regulating region of the IB1 gene abolished the repression activity driven by REST in insulin-secreting beta  cells and relieved the low transcriptional activity of IB1 observed in unrelated cells. Moreover, transfection in non-beta and nonneuronal cell lines of an expression vector encoding REST lacking its transcriptional repression domain relieved IB1 promoter activity. Last, the REST-mediated repression of IB1 could be abolished by trichostatin A, indicating that deacetylase activity is required to allow REST repression. Taken together, these data establish a critical role for REST in the control of the tissue-specific expression of the human IB1 gene.

* Corresponding author. Mailing address: Department of Internal Medicine B, University Hospital CHUV, 1011 Lausanne, Switzerland. Phone: 41-21-314.09.60. Fax: 41-21-314.04.51. E-mail: gwaeber{at}chuv.hospvd.ch.

Molecular and Cellular Biology, November 2001, p. 7256-7267, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7256-7267.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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