Hypoxia-inducible factor-1 alpha (HIF-1 alpha) has a central role in neuroprotective responses to hypoxia in the brain. Hydroxylation of HIF-1 alpha by prolyl-hydroxylase PHD and aspargynyl-hydroxylase FIH (factor inhibiting HIF-1 alpha) causes proteasomal degradation and transcriptional inhibition of HIF-1 alpha. Siah ubiquitin ligases regulate the abundance of PHD via targeting for proteasomal degradation. The present study identified Siah-1 as a binding partner for another hydroxylase FIH. Siah-1 and FIH coimmunoprecipitated each other in mammalian cells. Siah-1 was found both to interact with the JmjC domain of FIH through its substrate-binding domain and to specifically ubiquitinate FIH via its RING finger domain. Siah-1 facilitated FIH degradation via the ubiquitin-proteasome pathway under hypoxic conditions. Such findings suggest that Siah ubiquitin ligases might play a role as up-stream regulators of both hydroxylases for HIF-1 alpha, i.e., PHD and FIH, by targeting them for proteasomal degradation, leading to increased HIF-1 alpha abundance, and transcriptional activity in hypoxia. (c) 2006 Elsevier Inc. All rights reserved.