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J. Biol. Chem., Vol. 281, Issue 24, 16649-16655, June 16, 2006

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The Presenilin-2 Loop Peptide Perturbs Intracellular Ca²⁺ Homeostasis and Accelerates Apoptosis^*

Chuanxi Cai, Peihui Lin, King-Ho Cheung, Na Li, Christina Levchook, Zui Pan, Christopher Ferrante, Gabrielle L. Boulianne^¶, J. Kevin Foskett, David Danielpour^||, and Jianjie Ma¹

From the Department of Physiology and Biophysics, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, the ^¶Program in Developmental Biology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1X8, Canada, the Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6085, and the ^||Ireland Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106

In cells undergoing apoptosis, a 22-amino-acid presenilin-2-loop peptide (PS2-LP, amino acids 308–329 in presenilin-2) is generated through cleavage of the carboxyl-terminal fragment of presenilin-2 by caspase-3. The impact of PS2-LP on the progression of apoptosis, however, is not known. Here we show that PS2-LP is a potent inducer of the mitochondrial-dependent cell death pathway when transduced as a fusion protein with HIV-TAT. Biochemical and functional studies demonstrate that TAT-PS2-LP can interact with the inositol 1,4,5-trisphosphate receptor and activate Ca²⁺ release from the endoplasmic reticulum. These results indicate that PS2-LP-mediated alteration of intracellular Ca²⁺ homeostasis may be linked to the acceleration of apoptosis. Therefore, targeting the function of PS2-LP could provide a useful therapeutic tool for the treatment of cancer and degenerative diseases.

Received for publication, November 8, 2005 , and in revised form, March 27, 2006.

^* This work was supported by Grants R01-CA95379, R01-A1555G, R01-HL69000 (to J. M.), and R01-GM056328 (to J. K. F.) from the National Institutes of Health and a UMDNJ-Foundation Research grant (to Z. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Physiology and Biophysics, Robert Wood Johnson Medical School, 675 Hoes Ln., Piscataway, NJ 08854. Tel.: 732-235-4494; Fax: 732-235-4483; E-mail: maj2{at}umdnj.edu.

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