HIF-1α protein is upregulated in HIF-2α depleted cells via enhanced translation

The hypoxia-inducible factors HIF-1 and HIF-2 are primarily regulated via stabilization of their respective alpha-subunits under hypoxic conditions. Previously, compensatory upregulation of one HIF-alpha-subunit upon depletion of the other alpha-subunit was described, yet the underlying mechanism remained elusive. Here we provide evidence that enhanced HIF-1 alpha protein expression in HIF-2 alpha knockdown (k/d) cells neither results from elevated HIF-1 alpha mRNA expression, nor from increased HIF-1 alpha protein stability. Instead, we identify enhanced HIF-1 alpha translation as molecular mechanism. Moreover, we found elevated levels of the RNA-binding protein HuR and provide evidence that HuR is critical for the compensatory HIF-1 alpha regulation in HIF-2 alpha k/d cells. (C) 2012 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.