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Vol. 17, Issue 4, 1549-1558, April 2006

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Calpain Mediates a von Hippel-Lindau Protein–independent Destruction of Hypoxia-inducible Factor-1

Jie Zhou ^*, Roman Köhl ^*, Barbara Herr ^*, Ronald Frank , and Bernhard Brüne ^*

^* Institute of Biochemistry I, Faculty of Medicine, Johann Wolfgang Goethe-University Frankfurt, 60590 Frankfurt, Germany; Department of Chemical Biology, German Research Center for Biotechnology, 38124 Braunschweig, Germany

Submitted August 17, 2005; Revised December 27, 2005; Accepted January 10, 2006
Monitoring Editor: Suzanne Pfeffer

Hypoxia-inducible factor 1 (HIF-1) is controlled through stability regulation of its alpha subunit, which is expressed under hypoxia but degraded under normoxia. Degradation of HIF-1 requires association of the von Hippel Lindau protein (pVHL) to provoke ubiquitination followed by proteasomal digestion. Besides hypoxia, nitric oxide (NO) stabilizes HIF-1 under normoxia but destabilizes the protein under hypoxia. To understand the role of NO under hypoxia we made use of pVHL-deficient renal carcinoma cells (RCC4) that show a high steady state HIF-1 expression under normoxia. Exposing RCC4 cells to hypoxia in combination with the NO donor DETA-NO (2,2'-(hydroxynitrosohydrazono) bis-ethanimine), but not hypoxia or DETA-NO alone, decreased HIF-1 protein and attenuated HIF-1 transactivation. Mechanistically, we noticed a role of calpain because calpain inhibitors reversed HIF-1 degradation. Furthermore, chelating intracellular calcium attenuated HIF-1 destruction by hypoxia/DETA-NO, whereas a calcium increase was sufficient to lower the amount of HIF-1 even under normoxia. An active role of calpain in lowering HIF-1 amount was also evident in pVHL-containing human embryonic kidney cells when the calcium pump inhibitor thapsigargin reduced HIF-1 that was stabilized by the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG). We conclude that calcium contributes to HIF-1 destruction involving the calpain system.

Address correspondence to: Bernhard Brüne (bruene{at}zbc.kgu.de).

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