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MBC in Press, published online ahead of print January 18, 2006
Mol. Biol. Cell 10.1091/mbc.E05-08-0770

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Submitted on August 17, 2005
Revised on December 27, 2005
Accepted on January 10, 2006

Calpain Mediates a von Hippel-Lindau Protein-independent Destruction of Hypoxia-inducible Factor-1{alpha}

Jie Zhou,* Roman Köhl,* Barbara Herr,* Ronald Frank,{dagger} and Bernhard Brüne*

*Institute of Biochemistry I, Faculty of Medicine, Johann Wolfgang Goethe-University Frankfurt, 60590 Frankfurt, Germany; {dagger}Department of Chemical Biology, GBF (German Research Center for Biotechnology), 38124 Braunschweig, Germany

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{alpha} requires association of the von Hippel Lindau protein (pVHL) to provoke ubiquitination followed by proteasomal digestion. Besides hypoxia, nitric oxide (NO) stabilizes HIF-1{alpha} 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{alpha} expression under normoxia. Exposing RCC4 cells to hypoxia in combination with the NO donor DETA-NO (2,2'-(hydroxynitroso-hydrazono) bis-ethanimine), but not hypoxia or DETA-NO alone, decreased HIF-1{alpha} protein and attenuated HIF-1 transactivation. Mechanistically, we noticed a role of calpain because calpain inhibitors reversed HIF-1{alpha} degradation. Furthermore, chelating intracellular calcium attenuated HIF-1{alpha} destruction by hypoxia/DETA-NO while a calcium increase was sufficient to lower the amount of HIF-1{alpha} even under normoxia. An active role of calpain in lowering HIF-1{alpha} amount was also evident in pVHL-containing human embryonic kidney cells when the calcium pump inhibitor thapsigargin reduced HIF-1{alpha} that was stabilized by the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG). We conclude that calcium contributes to HIF-1{alpha} destruction involving the calpain system.

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




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