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Combining Non-reducing SDS-PAGE Analysis and Chemical Crosslinking to Detect Multimeric Complexes Stabilized by Disulfide Linkages in Mammalian Cells in Culture
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Activation of the lifespan regulator p66Shc through reversible disulfide bond formation

Melanie Gertz1, Frank Fischer, Dirk Wolters

  • 1Departments of Physiological Chemistry and Analytical Chemistry, Ruhr-University Bochum, Universitätsstrasse 150, 44801 Bochum, Germany.

Proceedings of the National Academy of Sciences of the United States of America
|April 17, 2008
PubMed

Insights

Cellular stress triggers apoptosis via the p66Shc protein

Area of Science:

  • Molecular biology
  • Cellular signaling
  • Aging research

Background:

  • Organismal lifespan and cell fate are regulated by complex signaling networks.
  • Dysfunctional signaling contributes to aging-related diseases.
  • Cellular apoptosis, induced by p66Shc, is a protective mechanism against cellular stress.

Purpose of the Study:

  • To elucidate the mechanisms of p66Shc action and regulation.
  • To identify the function of the p66Shc-specific N terminus.

Main Methods:

  • Investigated the role of the p66Shc N terminus in apoptosis.
  • Analyzed the activation mechanism of the p66Shc redox module.
  • Examined the effects of glutathione and thioredoxins on p66Shc activity.

Main Results:

  • The p66Shc N terminus functions as a redox module initiating apoptosis.
  • Reversible tetramerization via disulfide bonds activates this module.
  • Glutathione and thioredoxins reduce and inactivate p66Shc.

Conclusions:

  • p66Shc acts as a thiol-based redox sensor, initiating apoptosis when cellular defenses are overwhelmed.
  • This system links cellular stress to apoptosis, impacting aging and disease.

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