SIAH-2 (seven in absentia homolog 2) is an E3 ligase that catalyzes ubiquitination and proteasome-mediated degradation of protein substrates. SIAH-2 encodes a 324 amino acid protein that shares 77% identity with human SIAH-1 and 68% identity with the Drosophila sina (seven in absentia) gene, on which development of the Drosophila R7 photoreceptor is dependent. SIAH-2 targets TRAF2 (which regulates cell responses to stress and cytokines through the regulation of key stress-signaling cascades) for degradation under stress conditions such as hypoxia. It targets HIF-1α prolyl hydroxylase 3 (PHD3) for degradation upon exposure to hypoxic conditions, which coincides with an increase in SIAH-2 transcription. SIAH-2 can decrease TNF-α-dependent induction of JNK activity and transcriptional activation of NFκB. SIAH-2 null mice subjected to hypoxia display an impaired respiratory response and reduced levels of hemoglobin.