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

doi:10.1128/MCB.21.21.7256-7267.2001

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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-terminalkinase (JNK). IB1 expression is mostly restricted to the endocrinepancreas and to the central nervous system. Herein, we exploredthe transcriptional mechanism responsible for this preferentialislet and neuronal expression of IB1. A 731-bp fragment of the5' regulatory region of the human MAPK8IP1 gene was isolated froma human BAC library and cloned upstream of a luciferase reportergene. This construct drove high transcriptional activity in bothinsulin-secreting and neuron-like cells but not in unrelated celllines. Sequence analysis of this promoter region revealed thepresence of a neuron-restrictive silencer element (NRSE) knownto bind repressor zinc finger protein REST. This factor is notexpressed in insulin-secreting and neuron-like cells. By mobilityshift assay, we confirmed that REST binds to the NRSE presentin the IB1 promoter. Once transiently transfected in $beta$ -cell lines,the expression vector encoding REST repressed IB1 transcriptionalactivity. The introduction of a mutated NRSE in the 5' regulatingregion of the IB1 gene abolished the repression activity drivenby REST in insulin-secreting $beta$ cells and relieved the low transcriptionalactivity of IB1 observed in unrelated cells. Moreover, transfectionin non- $beta$ and nonneuronal cell lines of an expression vector encodingREST lacking its transcriptional repression domain relieved IB1promoter activity. Last, the REST-mediated repression of IB1 couldbe abolished by trichostatin A, indicating that deacetylase activityis required to allow REST repression. Taken together, these dataestablish a critical role for REST in the control of the tissue-specificexpression of the human IB1gene.

^* 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.

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