Apoptotic threshold is lowered by p53 transactivation of caspase-6
- *Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, and Departments of ‡Medicine, §Genetics, ¶Pharmacology, and ‖Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
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Communicated by Britton Chance, University of Pennsylvania School of Medicine, Philadelphia, PA (received for review January 11, 2002)
Abstract
Little is known about how a cell's apoptotic threshold is controlled after exposure to chemotherapy, although the p53 tumor suppressor has been implicated. We identified executioner caspase-6 as a transcriptional target of p53. The mechanism involves DNA binding by p53 to the third intron of the caspase-6 gene and transactivation. A p53-dependent increase in procaspase-6 protein level allows for an increase in caspase-6 activity and caspase-6-specific Lamin A cleavage in response to Adriamycin exposure. Specific inhibition of caspase-6 blocks cell death in a manner that correlates with caspase-6 mRNA induction by p53 and enhances long-term survival in response to a p53-mediated apoptotic signal. Caspase-6 is an executioner caspase found directly regulated by p53, and the most downstream component of the death pathway controlled by p53. The induction of caspase-6 expression lowers the cell death threshold in response to apoptotic signals that activate caspase-6. Our results provide a potential mechanism of lowering the death threshold, which could be important for chemosensitization.
Footnotes
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↵ ** To whom reprint requests should be addressed. E-mail: wafik{at}mail.med.upenn.edu.
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Present address: Curagen Corporation, Branford, CT 06406.
- Abbreviations:
- VEID–FMK,
- benzyloxylcarbonyl-valine-glutamate-isoleucine-aspartate-fluoromethyl ketone;
- moi,
- multiplicity of infection
- Copyright © 2002, The National Academy of Sciences
