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The Journal of Neuroscience, June 1, 2003, 23(11):4519-4526

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Inducible cAMP Early Repressor, an Endogenous Antagonist of cAMP Responsive Element-Binding Protein, Evokes Neuronal Apoptosis In Vitro

Jacek Jaworski,^1 * Barbara Mioduszewska,^1,3 * Amelia Sánchez-Capelo,² Izabela Figiel,¹ Agata Habas,^4,5 Agata Gozdz,^4,5 Tomasz Proszynski,¹ Michal Hetman,^1,4,5 Jacques Mallet,² and Leszek Kaczmarek¹

¹ Department of Molecular and Cellular Neurobiology, Nencki Institute, Warsaw 02-093, Poland, ² Laboratoire de Genetique Moleculaire de la Neurotransmission et des Processus Neurodegeneratifs, Unité Mixte de Recherche 9923, Centre National de la Recherche Scientifique, Paris 75013, France, ³ Warsaw Agriculture University, Veterinary School, Warsaw 02-787, Poland, ⁴ Kentucky Spinal Cord Injury Research Center and Department of Neurological Surgery, University of Louisville, Louisville, Kentucky 40292, and ⁵ Laboratory of Neuropathology, International Institute of Molecular and Cellular Biology, Warsaw 02-109, Poland

Active CREB (cAMP responsive element-binding protein) transcription factor is crucial for neuronal survival. Several members of the CREM/ICER (cAMP responsive element modulator/inducible cAMP early repressor) protein family may act as endogenous CREB antagonists. However, their involvement in a process of programmed cell death remains unexplored. Here we report that ICER may play such a role in neuronal apoptosis because it is upregulated in apoptotic neurons in vitro, and overexpression of ICER, delivered in adenoviral vector, evokes programmed cell death of three different kinds of cultured neurons, namely those derived from hippocampal dentate gyrus, cerebral cortex, and superior cervical ganglion. Reporter gene assay with a promoter containing a CREB-responsive sequence revealed a decrease in both basal and induced CRE-dependent gene expression in neurons overexpressing ICER. Finally, the level of expression of the anti-apoptotic protein Bcl-2, a well known CREB target, was markedly diminished in ICER-treated neurons. We suggest that the naturally occurring CREB functional antagonist ICER may have a specific function in programmed cell death of neurons, probably by silencing the expression of anti-apoptotic genes.

Key words: ICER; CREB; neuronal apoptosis; gene expression; Bcl-2; adenoviral vectors

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Received Oct. 30, 2002; revised Mar. 11, 2003; accepted Mar. 13, 2003.

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