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Molecular and Cellular Biology, January 2008, p. 718-731, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.01338-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis{triangledown}

Robert D. Guzy,1 Bhumika Sharma,1 Eric Bell,2 Navdeep S. Chandel,2 and Paul T. Schumacker1,2*

Department of Pediatrics, Division of Neonatology,1 Department of Medicine, Division of Pulmonary and Critical Care, Northwestern University, Chicago, Illinois 606112

Received 25 July 2007/ Returned for modification 20 August 2007/ Accepted 19 October 2007

Mitochondrial complex II is a tumor suppressor comprised of four subunits (SdhA, SdhB, SdhC, and SdhD). Mutations in any of these should disrupt complex II enzymatic activity, yet defects in SdhA produce bioenergetic deficiency while defects in SdhB, SdhC, or SdhD induce tumor formation. The mechanisms underlying these differences are not known. We show that the inhibition of distal subunits of complex II, either pharmacologically or via RNA interference of SdhB, increases normoxic reactive oxygen species (ROS) production, increases hypoxia-inducible factor alpha (HIF-{alpha}) stabilization in an ROS-dependent manner, and increases growth rates in vitro and in vivo without affecting hypoxia-mediated activation of HIF-{alpha}. Proximal pharmacologic inhibition or RNA interference of complex II at SdhA, however, does not increase normoxic ROS production or HIF-{alpha} stabilization and results in decreased growth rates in vitro and in vivo. Furthermore, the enhanced growth rates resulting from SdhB suppression are inhibited by the suppression of HIF-1{alpha} and/or HIF-2{alpha}, indicating that the mechanism of SdhB-induced tumor formation relies upon ROS production and subsequent HIF-{alpha} activation. Therefore, differences in ROS production, HIF proliferation, and cell proliferation contribute to the differences in tumor phenotype in cells lacking SdhB as opposed to those lacking SdhA.

* Corresponding author. Mailing address: Department of Pediatrics, Northwestern University, 303 East Chicago Ave., Ward Bldg. 12-191, Chicago, IL 60611. Phone: (312) 503-1475. Fax: (312) 503-2441. E-mail: p-schumacker{at}northwestern.edu

{triangledown} Published ahead of print on 29 October 2007.

Molecular and Cellular Biology, January 2008, p. 718-731, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.01338-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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