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The Journal of Neuroscience, July 7, 2004, 24(27):6189-6201; doi:10.1523/JNEUROSCI.1426-04.2004

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Cellular/Molecular
Cloning of a Novel Apaf-1-Interacting Protein: A Potent Suppressor of Apoptosis and Ischemic Neuronal Cell Death

Guodong Cao,^1 * Michael Xiao,^1,2 * Fengyan Sun,^1,3 Xiao Xiao,² Wei Pei,¹ Juan Li,² Steven H. Graham,^1,5 Roger P. Simon,⁴ and Jun Chen^1,5

Departments of ¹Neurology and ²Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, ³National Key Laboratory for Medical Neurobiology, Fudan University School of Medicine, Shanghai, China, ⁴R. S. Dow Neurobiology Laboratories, Legacy Research, and Departments of Neurology, Physiology, and Pharmacology, Oregon Health Science University, Portland, Oregon 97232, and ⁵Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, Pennsylvania 15261

Cytochrome c-initiated activation of apoptotic protease activating factor-1 (Apaf-1) is a key step in the mitochondrial-signaling pathway for the activation of death-executing caspases in apoptosis. This signaling pathway has been implicated in the pathophysiology of various neurological disorders, including ischemic brain injury. In this study, we have cloned a novel rat gene product, designated as Apaf-1-interacting protein (AIP), which functions as a dominant-negative inhibitor of the Apaf-1-caspase-9 pathway. AIP is constitutively expressed in the brain, but at substantially lower levels than Apaf-1 and caspase-9. AIP can directly bind to Apaf-1 in vitro through its N-terminal caspase-recruiting domain, and this protein interaction was increased in cells undergoing apoptosis. Cytosolic extracts from cells overexpressing AIP were highly resistant to cytochrome c- dATP-induced activation of caspase-9 and caspase-3. Gene transfection of AIP into cell lines, including the neuronal-differentiated PC12 cells, potently suppressed apoptosis induced by various pro-apoptotic stimuli. To further investigate the functional role of AIP in primary neurons and in the brain, an adeno-associated virus (AAV) vector carrying the AIP cDNA was constructed. AAV-mediated overexpression of AIP in primary cortical- hippocampal neurons markedly reduced cell death and caspase-3 activation triggered by protein kinase C inhibition, DNA damage, or oxygen- glucose deprivation. Moreover, intracerebral infusion of the AAV vector resulted in robust AIP expression in the hippocampus and significantly promoted CA1 neuronal survival after transient global cerebral ischemia. These results suggest that molecular targeting of the Apaf-1-caspase-9 signaling pathway may be a feasible neuroprotective strategy to enhance the endogenous threshold for caspase activation and prevent neuronal loss in stroke and related disorders.

Key words: cerebral ischemia; mitochondria; AAV; Apaf-1; apoptosome; caspase-9

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Received April 15, 2004; revised May 20, 2004; accepted May 25, 2004.

This article has been cited by other articles:

				B. R.S. Broughton, D. C. Reutens, and C. G. Sobey Apoptotic Mechanisms After Cerebral Ischemia Stroke, May 1, 2009; 40(5): e331 - e339. [Abstract] [Full Text] [PDF]

				R. A. Stetler, G. Cao, Y. Gao, F. Zhang, S. Wang, Z. Weng, P. Vosler, L. Zhang, A. Signore, S. H. Graham, et al. Hsp27 Protects against Ischemic Brain Injury via Attenuation of a Novel Stress-Response Cascade Upstream of Mitochondrial Cell Death Signaling J. Neurosci., December 3, 2008; 28(49): 13038 - 13055. [Abstract] [Full Text] [PDF]

				G. Cao, J. Xing, X. Xiao, A. K. F. Liou, Y. Gao, X.-M. Yin, R. S. B. Clark, S. H. Graham, and J. Chen Critical Role of Calpain I in Mitochondrial Release of Apoptosis-Inducing Factor in Ischemic Neuronal Injury J. Neurosci., August 29, 2007; 27(35): 9278 - 9293. [Abstract] [Full Text] [PDF]

				J. Luo, H. Chen, D. B. Kintner, G. E. Shull, and D. Sun Decreased Neuronal Death in Na+/H+ Exchanger Isoform 1-Null Mice after In Vitro and In Vivo Ischemia J. Neurosci., December 7, 2005; 25(49): 11256 - 11268. [Abstract] [Full Text] [PDF]

				D. Lindholm and U. Arumae Cell differentiation: reciprocal regulation of Apaf-1 and the inhibitor of apoptosis proteins J. Cell Biol., October 25, 2004; 167(2): 193 - 195. [Abstract] [Full Text] [PDF]

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