The transcriptional repressor REST determines the cell-specific expressionof the human MAPK8IP1 gene encoding IB1 (JIP-1)

Islet-brain 1 (IB1) is the human and rat homologue of JIP-1, a scaffold pro tein 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 t his preferential islet and neuronal expression of IB1. A 731-bp fragment of the 5' regulatory region of the human MAPK81P1 gene was isolated from a hu man BAC library and cloned upstream of a luciferase reporter gene. This con struct drove high transcriptional activity in both insulin-secreting and ne uron-like cells but not in unrelated cell lines. Sequence analysis of this promoter region revealed the presence of a neuron-restrictive silencer elem ent (NRSE) known to bind repressor zinc finger protein REST. This factor is not expressed in insulin-secreting and neuron-like cells. By mobility shif t assay, we confirmed that REST binds to the NRSE present in the IB1 promot er. 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 re pression activity driven by REST in insulin-secreting beta cells and reliev ed the low transcriptional activity of IB1 observed in unrelated cells. Mor eover, transfection in non-beta and nonneuronal cell lines of an expression vector encoding REST lacking its transcriptional repression domain relieve d IB1 promoter activity. Last, the REST-mediated repression of IB1 could be abolished by trichostatin A, indicating that deacetylase activity is requi red to allow REST repression. Taken together, these data establish a critic al role for REST in the control of the tissue-specific expression of the hu man IB1 gene.