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Suppression of ß-Amyloid Precursor Protein Signaling into the Nucleus by Estrogens Mediated through Complex Formation between the Estrogen Receptor and Fe65

Junying Bao,^1,3 Chuanhai Cao,² Xiaohui Zhang,^1,3 Feng Jiang,^1,3, Santo V. Nicosia,^1,3 and Wenlong Bai^1,3*

Departments of Pathology and of Cell Biology and Molecular Oncology, USF College of Medicine,¹ Programs of Molecular Oncology and Drug Discovery, H. Lee Moffitt Cancer Center, Tampa, Florida 33612-4799,³ Department of Medical Microbiology and Johnnie B. Byrd, Sr., Alzheimer's Center & Research Institute, USF College of Medicine, Tampa, Florida 33612-4799²

Received 13 July 2006/ Returned for modification 15 August 2006/ Accepted 16 November 2006

The C-terminal fragment of the ß-amyloid precursor protein produced after cleavage by -secretase, namely, APPct or AICD, has been shown to form a multimeric complex with the adaptor protein Fe65 and to regulate transcription through the recruitment of the histone acetyltransferase Tip60. The present study shows that 17ß-estradiol inhibits the transcriptional and apoptotic activities of the APPct complex by a process involving the interaction of estrogen receptor alpha (ER) with Fe65. ER-Fe65 complexes were detected both in vitro and in the mouse brain, and recruitment of ER to the promoter of an APPct target gene (KAI1) was demonstrated. Our studies reveal a novel mechanism of estrogen action, which may explain the well-known neuroprotective functions of estrogens as well as the complex role of this female hormone in the pathogenesis of neuronal degeneration diseases.

Published ahead of print on 27 November 2006.

Present address: Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306-4300.

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