Siah2-null mice subjected to hypoxia displayed an impaired hyperpneic respiratory response and reduced levels of hemoglobin. In 293T cells, SIAH2 targeting of PHD3 for degradation increased upon exposure to even mild hypoxic conditions, which coincided with increased SIAH2 transcription. Hypoxia-induced Hif1a expression was completely inhibited in Siah1a/Siah2-null cells, yet could be rescued upon inhibition of Phd3 by RNA interference. Siah2-null mouse fibroblasts exhibited prolonged Phd3 half-life, resulting in lower levels of Hif1a expression during hypoxia. (2004) demonstrated that PHD1 (606424) and PHD3 (606426) abundance is regulated via their targeting for proteasome-dependent degradation by the E3 ubiquitin ligases SIAH1 and SIAH2 under hypoxia conditions. Prolyl hydroxylation of HIF1A (603348) by prolyl hydroxylase domain-containing proteins (PHDs) is prerequisite for HIF1A degradation. (2004) concluded that control of PHD1 and PHD3 by SIAH1 and SIAH2 constitutes another level of complexity in the regulation of HIF1A during hypoxia. (2004) demonstrated that PHD1 ( 606424) and PHD3 ( 606426) abundance is regulated via their targeting for proteasome-dependent degradation by the E3 ubiquitin ligases SIAH1 and SIAH2 under hypoxia conditions. Prolyl hydroxylation of HIF1A ( 603348) by prolyl hydroxylase domain-containing proteins (PHDs) is prerequisite for HIF1A degradation.

Their substantial evolutionary conservation, role in specifying cell fate, and activation in apoptotic cells suggested that the SIAH proteins have important roles in vertebrate development. While a previous study suggested that sina is a nuclear protein, epitope-labeled sina and SIAH1 proteins were found in the cytoplasm of Drosophila and mammalian cells. However, 1 of 3 murine homologs, Siah1b, was strongly induced in fibroblasts undergoing apoptotic cell death. (1997) found that SIAH1 and SIAH2 are expressed in many normal and neoplastic tissues, and only subtle differences in their expression were noted.

Half life e3 1997