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1652175 
Journal Article 
Calpain mediates a von Hippel-Lindau protein-independent destruction of hypoxia-inducible factor-1 alpha 
Zhou, J; Kohl, R; Herr, B; Frank, R; Brune, B 
2006 
1 
Molecular Biology of the Cell
ISSN: 1059-1524
EISSN: 1939-4586 
17 
4 
1549-1558 
16421254 
WOS:000236657900006 
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'-(hydroxynitrosohydrazono) 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, whereas 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.