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First published online 15 April 2003
doi: 10.1242/jcs.00427

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Journal of Cell Science 116, 2247-2260 (2003)
doi: 10.1242/jcs.00427

Research Article

HIF-1{alpha} mRNA and protein upregulation involves Rho GTPase expression during hypoxia in renal cell carcinoma

Sandra Turcotte, Richard R. Desrosiers and Richard Béliveau*

Laboratoire de médecine moléculaire, Hôpital Sainte-Justine, Université du Québec à Montréal, CP 8888, Succursale centre-ville, Montréal, Québec, Canada H3C 3P8

* Author for correspondence (e-mail: oncomol{at}nobel.si.uqam.ca)

Accepted 12 February 2003

The small G proteins of the Rho family are involved in reorganization of the actin cytoskeleton, cell migration and in the regulation of gene transcription. Hypoxia-induced ATP depletion results in the disruption of actin organization which could affect Rho functions. In solid tumors, regions with low oxygen tension stimulate angiogenesis in order to increase oxygen and nutrient supply. This process is mediated by stabilization of the transcriptional factor hypoxia inducible factor 1 (HIF-1), which increases vascular endothelial growth factor (VEGF) production. In this study, we investigated the activities of Rho proteins, which are key regulators of cytoskeleton organization during hypoxia in renal cell carcinoma. Caki-1 cells were exposed to hypoxia (1% O2) and exhibited increased Cdc42, Rac1 and RhoA protein expression. Immunoprecipitation of metabolically labelled RhoA showed that overexpression was at least due to neo-synthesis. The Rho GTPases overexpressed during hypoxia were mainly located at membranes and pull-down assays demonstrated that they were active since they bound GTP. RT-PCR analysis indicated that the increase in RhoA protein expression was also reflected at the mRNA level. Overexpression and activation of Rho proteins were downstream of, and dependent on, the production of reactive oxygen species (ROS) since, in the presence of an inhibitor, both the rise of ROS and upregulation of Rho proteins were abolished. Importantly, preincubation of cells with the toxin C3, which inhibits RhoA, reduced HIF-1{alpha} protein accumulation by 84% during hypoxia. Together, these results support a model where ROS upregulate Rho protein expression and where active RhoA is required for HIF-1{alpha} accumulation during hypoxia.

Key words: Hypoxia, Hypoxia inductible factor 1, Rho proteins, Carcinoma cells, Reactive oxygen species




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