Activation of the lifespan regulator p66Shc through reversible disulfide bond formation
- Departments of *Physiological Chemistry and
- †Analytical Chemistry, Ruhr-University Bochum, Universitätsstrasse 150, 44801 Bochum, Germany
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Communicated by Robert Huber, Max Planck Institute for Biochemistry, Martinsried, Germany, February 22, 2008 (received for review December 10, 2007)
Abstract
Cell fate and organismal lifespan are controlled by a complex signaling network whose dysfunction can cause a variety of aging-related diseases. An important protection against these failures is cellular apoptosis, which can be induced by p66Shc in response to cellular stress. The precise mechanisms of p66Shc action and regulation and the function of the p66Shc-specific N terminus remain to be identified. Here, we show that the p66Shc N terminus forms a redox module responsible for apoptosis initiation, and that this module can be activated through reversible tetramerization by forming two disulfide bonds. Glutathione and thioredoxins can reduce and inactivate p66Shc, resulting in a thiol-based redox sensor system that initiates apoptosis once cellular protection systems cannot cope anymore with cellular stress.
Footnotes
- ‡To whom correspondence should be addressed. E-mail: clemens.steegborn{at}rub.de
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Author contributions: M.G. and C.S. designed research; M.G., F.F., and D.W. performed research; M.G., F.F., D.W., and C.S. analyzed data; and M.G. and C.S. wrote the paper.
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The authors declare no conflict of interest.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0800691105/DCSupplemental.
- © 2008 by The National Academy of Sciences of the USA
