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Driving innovations in manufacturing: Open Access research from DMEM

Strathprints makes available Open Access scholarly outputs by Strathclyde's Department of Design, Manufacture & Engineering Management (DMEM).

Centred on the vision of 'Delivering Total Engineering', DMEM is a centre for excellence in the processes, systems and technologies needed to support and enable engineering from concept to remanufacture. From user-centred design to sustainable design, from manufacturing operations to remanufacturing, from advanced materials research to systems engineering.

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Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF- prolylhydroxylase

Selak, M.A. and Armour, S.M. and MacKenzie, E.D. and Boulahbel, H. and Watson, D.G. and Mansfield, K.D. and Pan, Y. and Simon, M.C. and Thompson, C.B. and Gottlieb, E. (2005) Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF- prolylhydroxylase. Cancer Cell, 7. pp. 77-85. ISSN 1878-3686

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Abstract

Several mitochondrial proteins are tumor suppressors. These include succinate dehydrogenase (SDH) and fumarate hydratase, both enzymes of the tricarboxylic acid (TCA) cycle. However, to date, the mechanisms by which defects in the TCA cycle contribute to tumor formation have not been elucidated. Here we describe a mitochondrion-to-cytosol signaling pathway that links mitochondrial dysfunction to oncogenic events: succinate, which accumulates as a result of SDH inhibition, inhibits HIF-α prolyl hydroxylases in the cytosol, leading to stabilization and activation of HIF-1α. These results suggest a mechanistic link between SDH mutations and HIF-1α induction, providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations.