Alternative titles; symbols
HGNC Approved Gene Symbol: SIAH2
Cytogenetic location: 3q25.1 Genomic coordinates (GRCh38): 3:150,741,125-150,763,169 (from NCBI)
Hu et al. (1997) demonstrated the means by which signal transduction events regulate cell fate decisions in a multicellular organism. Development of the Drosophila R7 photoreceptor is dependent on the 'seven in absentia' (sina) gene. The authors characterized 2 highly conserved human homologs of sina, termed SIAH1 (602212) and SIAH2 (602213). SIAH2 encodes a 324-amino acid protein that shares 68% identity with Drosophila sina and 77% identity with human SIAH1.
Hu et al. (1997) found that SIAH1 and SIAH2 are expressed in many normal and neoplastic tissues, and only subtle differences in their expression were noted. However, 1 of 3 murine homologs, Siah1b, was strongly induced in fibroblasts undergoing apoptotic cell death. 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. 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.
Prolyl hydroxylation of HIF1A (603348) by prolyl hydroxylase domain-containing proteins (PHDs) is prerequisite for HIF1A degradation. Nakayama et al. (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. Siah2-null mouse fibroblasts exhibited prolonged Phd3 half-life, resulting in lower levels of Hif1a expression during hypoxia. Hypoxia-induced Hif1a expression was completely inhibited in Siah1a/Siah2-null cells, yet could be rescued upon inhibition of Phd3 by RNA interference. In 293T cells, SIAH2 targeting of PHD3 for degradation increased upon exposure to even mild hypoxic conditions, which coincided with increased SIAH2 transcription. Siah2-null mice subjected to hypoxia displayed an impaired hyperpneic respiratory response and reduced levels of hemoglobin. Nakayama et al. (2004) concluded that control of PHD1 and PHD3 by SIAH1 and SIAH2 constitutes another level of complexity in the regulation of HIF1A during hypoxia.
Hu et al. (1997) mapped the SIAH2 gene to 3q25 by fluorescence in situ hybridization.
Hu, G., Chung, Y.-L., Glover, T., Valentine, V., Look, A T., Fearon, E. R. Characterization of human homologs of the Drosophila seven in absentia (sina) gene. Genomics 46: 103-111, 1997. [PubMed: 9403064] [Full Text: https://doi.org/10.1006/geno.1997.4997]
Nakayama, K., Frew, I. J., Hagensen, M., Skals, M., Habelhah, H., Bhoumik, A., Kadoya, T., Erdjument-Bromage, H., Tempst, P., Frappell, P. B., Bowtell, D. D., Ronai, Z. Siah2 regulates stability of prolyl-hydroxylases, controls HIF1-alpha abundance, and modulates physiologic responses to hypoxia. Cell 117: 941-952, 2004. [PubMed: 15210114] [Full Text: https://doi.org/10.1016/j.cell.2004.06.001]