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1 Laboratoire de Medecine Moleculaire, Hopital Sainte-Justine, Universite du Quebec a Montreal, Montreal, Quebec, Canada
* To whom correspondence should be addressed. E-mail: oncomol{at}nobel.si.uqam.ca.
A key task for the multifunctional von Hippel-Lindau protein (pVHL) is to regulate the activity of the hypoxia-inducible factor 1
(HIF-1) by targeting it to the proteasome for degradation under normoxia. pVHL binding to HIF-1 is lost under low oxygen tension leading to transcription of several genes involved in hypoxia response. However, the regulation of pVHL by hypoxia remains to be investigated. Here, we evaluated the effects of hypoxia on pVHL expression in carcinoma and endothelial cells. We showed that hypoxia stimulates pVHL levels (2.5-fold) in renal Caki-1 cells expressing wild type VHL (VHL+/+). This up-regulation was independent of VHL status because hypoxia also increased pVHL expression in renal 786-O cells carrying mutated VHL (VHL-/-). Hypoxia did not affect pVHL expression in the endothelial cells tested. Hypoxia-induced pVHL in Caki-1 cells was RhoA-dependent because inhibition by exotoxin C3 prevented pVHL stimulation. Furthermore, the inhibition of Rho kinase by Y27632 blocked pVHL induction by hypoxia. During normoxia, pVHL expression was also induced in cells transfected with the dominant-active RhoA. Furthermore, the disruption of actin organization by chemical agents or by hypoxia treatment stimulated pVHL expression in kidney cells. On other hand, the inhibition of MAP kinases p38 and JNK but not MEK1/2 reduced pVHL up-regulation by 30% and 72%, respectively, during hypoxia, supporting a significant role for these signalling pathways. Interestingly, the expression and phosphorylation of c-Jun were stimulated in cells transfected with the dominant-active RhoA. Together, these findings demonstrate that hypoxia induces pVHL expression in renal cancer cells, and this induction is
mediated by RhoA-dependent pathways.
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