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Vol. 14, Issue 8, 3082-3096, August 2003

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The Tumor Suppressor cybL, a Component of the Respiratory Chain, Mediates Apoptosis Induction

Timur Albayrak ^* , Volker Scherhammer ^* , Nicole Schoenfeld ^*, Erik Braziulis ^*, Thomas Mund ^*, Manuel K.A. Bauer ^*, Immo E. Scheffler , and Stefan Grimm ^* 

^* Max-Planck-Institute for Biochemistry, 82152 Martinsried, Germany; The Division of Biology, University of California, San Diego, La Jolla, California 92093-0322

Submitted October 4, 2002; Revised April 1, 2003; Accepted April 5, 2003
Monitoring Editor: Carl-Henrik Heldin

A genetic screen was established to clone apoptosis-inducing genes in a high-throughput format. It led to the isolation of several proapoptotic genes whose proteins are localized to mitochondria. One of the isolated genes is cytochrome b_L (cybL also known as SDHC, C_II-3, or QPs-1), a component of the respiratory chain complex II. It was further investigated because both cybL and another component of complex II, cybS, have recently been identified as tumor suppressor proteins, some of which act by controlling apoptosis. Our studies reveal that cell death induction by cybL expression is concomitant with a transient inhibition of complex II and the generation of reactive oxygen species. Importantly, cells that are constitutively deficient in cybL are resistant to a variety of proapoptotic cytostatic drugs and to the effects of the Fas receptor. Our results therefore identify complex II as a sensor for apoptosis induction and could explain the unexpected observation that complex II is inactivated in tumors.

These authors contributed equally to this work.

Corresponding author. E-mail address: sgrimm{at}biochem.mpg.de.

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