Proceedings of the National Academy of Sciences of the United States of America 2013 Oct 1;110(40):16181-16186. Epub 2013 Sep 16.
Xu, R; Paul, BD; Smith, DR; Tyagi, R; Rao, F; Khan, AB; Blech, DJ; Vandiver, MS; Harraz, MM; Guha, P; Ahmed, I; Sen, N; Gallagher, M; Snyder, SH
The Solomon H. Snyder Department of Neuroscience, Department of Pharmacology and Molecular Sciences, and Medical Scientist Training Program, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Profound induction of immediate early genes (IEGs) by neural activation is a critical determinant for plasticity in the brain, but intervening molecular signals are not well characterized. We demonstrate that inositol polyphosphate multikinase (IPMK) acts noncatalytically as a transcriptional coactivator to mediate induction of numerous IEGs. IEG induction by electroconvulsive stimulation is virtually abolished in the brains of IPMK-deleted mice, which also display deficits in spatial memory. Neural activity stimulates binding of IPMK to the histone acetyltransferase CBP and enhances its recruitment to IEG promoters. Interestingly, IPMK regulation of CBP recruitment and IEG induction does not require its catalytic activities. Dominant-negative constructs, which prevent IPMK-CBP binding, substantially decrease IEG induction. As IPMK is ubiquitously expressed, its epigenetic regulation of IEGs may influence diverse nonneural and neural biologic processes.