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J. Biol. Chem., Vol. 283, Issue 18, 12586-12594, May 2, 2008

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A Distinctive Physiological Role for IBβ in the Propagation of Mitochondrial Respiratory Stress Signaling^*

Gopa Biswas, Weigang Tang, Neal Sondheimer, Manti Guha, Seema Bansal, and Narayan G. Avadhani¹

From the Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and Section of Biochemical Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104

The NFBs regulate an array of physiological and pathological processes, including propagation of mitochondrial respiratory stress signaling in mammalian cells. We showed previously that mitochondrial stress activates NFB using a novel calcineurin-requiring pathway that is different from canonical or non-canonical pathways. This study shows that IBβ is essential for the propagation of mitochondrial stress signaling. Knock down of IBβ, but not IB, mRNA reduced the mitochondrial stress-mediated activation and nuclear translocation of cRel:p50, inhibiting expression of nuclear target genes RyR1 and cathepsin L. IBβ mRNA knock down also reduced resistance to staurosporine-induced apoptosis and decreased in vitro invasiveness. Induced receptor switching to insulin-like growth factor-1 receptor and increased glucose uptake are hallmarks of mitochondrial stress. IBβ mRNA knock down selectively abrogated the receptor switch and altered tubulin cytoskeletal organization. These results show that mitochondrial stress signaling uses an IBβ-initiated NFB pathway that is distinct from the other known NFB pathways. Furthermore, our results demonstrate the distinctive physiological roles of the two inhibitory proteins IBβ and IB.

Received for publication, December 24, 2007

^* This work was supported by National Institutes of Health Grant CA-22762. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce St., Philadelphia, PA 19104. Tel.: 215-898-8819; Fax: 215-573-6651; E-mail: narayan{at}vet.upenn.edu.

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