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Molecular and Cellular Biology, October 1999, p. 6788-6795, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Protein Kinase A Regulates Cholinergic Gene Expression in PC12 Cells: REST4 Silences the Silencing Activity of Neuron-Restrictive Silencer Factor/REST

Masahito Shimojo,1 Alice J. Paquette,2 David J. Anderson,2,3 and Louis B. Hersh1,*

Department of Biochemistry, University of Kentucky, Lexington, Kentucky,1 and Division of Biology2 and Howard Hughes Medical Institute,3 California Institute of Technology, Pasadena, California

Received 29 March 1999/Returned for modification 22 April 1999/Accepted 19 July 1999

The role of protein kinase A in regulating transcription of the cholinergic gene locus, which contains both the vesicular acetylcholine transporter gene and the choline acetyltransferase gene, was investigated in PC12 cells and a protein kinase A-deficient PC12 mutant, A126.1B2, in which transcription of the gene is reduced. The site of action of protein kinase A was localized to a neuron-restrictive silencer element/repressor element 1 (NRSE/RE-1) sequence within the cholinergic gene. Neuron-restrictive silencer factor (NRSF)/RE-1-silencing transcription factor (REST), the transcription factor which binds to NRSE/RE-1, was expressed at similar levels in both PC12 and A126.1B2 cells. Although nuclear extracts containing NRSF/REST from A126.1B2 exhibited binding to NRSE/RE-1, nuclear extracts from PC12 cells did not. The NRSF/REST isoform REST4 was expressed in PC12 cells but not in A126.1B2. REST4 inhibited binding of NRSF/REST to NRSE/RE-1 as determined by gel mobility shift assays. Coimmunoprecipitation was used to demonstrate interaction between NRSF/REST and REST4. Expression of recombinant REST4 in A126.1B2 was sufficient to transcriptionally activate the cholinergic gene locus. Thus, in PC12 cells, protein kinase A promotes the production of REST4, which inhibits repression of the cholinergic gene locus by NRSF/REST.

* Corresponding author. Mailing address: Department of Biochemistry, University of Kentucky, 800 Rose St., Lexington, KY 40536-0298. Phone: (606) 323-5549. Fax: (606) 323-1727. E-mail: lhersh{at}pop.uky.edu.

Molecular and Cellular Biology, October 1999, p. 6788-6795, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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