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Activation of the extrinsic caspase pathway in cultured cortical neurons requires p53‐mediated down‐regulation of the X‐linked inhibitor of apoptosis protein to induce apoptosis
Author(s) -
Tun Christina,
Guo Weiqun,
Nguyen Huy,
Yun Bomy,
Libby Randell T.,
Morrison Richard S.,
Garden Gwenn A.
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04609.x
Subject(s) - xiap , inhibitor of apoptosis , apoptosis , microbiology and biotechnology , inhibitor of apoptosis domain , caspase 3 , caspase 9 , biology , caspase , programmed cell death , biochemistry
Cultured cortical neurons exposed to the Human Immunodeficiency Virus gp120 coat protein undergo apoptosis involving activation of both caspase‐8 and caspase‐9. Additionally, gp120‐mediated neuronal apoptosis requires the pro‐apoptotic transcription factor p53. As caspase‐8‐induced apoptosis does not typically require p53, we examined the possibility of a novel role for p53 in caspase‐8 activation initiated by gp120. We observed that gp120 treatment of cultured cortical neurons induced caspase‐8 activity and Bid cleavage independently of p53, but induction of caspase‐3 enzymatic activity required p53 expression. These findings suggested the possibility that p53 down‐regulates a caspase‐3 inhibitor. We observed high‐level expression of the caspase‐3/9 inhibitor X‐linked inhibitor of apoptosis protein (XIAP) in cultured cortical neurons. Adenoviral expression of p53 or induction of endogenous p53 by camptothecin treatment reduced XIAP protein in neurons. Infection with a p53 expressing adenovirus increased expression of the mRNA for Omi/HtrA2, a protease that cleaves and inactivates XIAP. These findings suggest that p53 regulates neuronal apoptosis, in part, by suppressing the anti‐apoptotic protein XIAP via transcriptional activation of Omi/HtrA2.