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Gene Review

SIAH1  -  siah E3 ubiquitin protein ligase 1

Homo sapiens

Synonyms: E3 ubiquitin-protein ligase SIAH1, HUMSIAH, Seven in absentia homolog 1, Siah-1, Siah-1a, ...
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Disease relevance of SIAH1


High impact information on SIAH1

  • New evidence suggests that at least two members of the family of hypoxia-inducible factor (HIF) prolyl hydroxylases that regulate HIF stability in response to oxygen (O2) availability are also targeted for proteosome-dependent degradation by the E3 ubiquitin ligases Siah1a and Siah2 [3].
  • Taken together, the data imply that the Sina/Siah proteins regulate DCC and perhaps other proteins via the ubiquitin-proteasome pathway [6].
  • Sina has a critical role in R7 photoreceptor development and shows upward of 85% amino acid identity with its mammalian homologs (termed Siahs), but the function of the Sina/Siah proteins has not been defined [6].
  • Siah-1, the human homolog of Drosophila seven in absentia, is a p53-inducible mediator of cell cycle arrest, tumor suppression, and apoptosis [7].
  • Here we have identified the RING finger protein Siah-1 as a protein interacting specifically with OBF-1 [8].

Biological context of SIAH1


Anatomical context of SIAH1

  • Further evidence that SIAH proteins may play a role in inclusion formation comes from the demonstration of SIAH immunoreactivity in Lewy bodies of PD patients [1].
  • Pharmacological inhibition and small interfering RNA suppression of GSK3beta greatly increased ubiquitylation and inclusion body formation by SIAH [13].
  • Transcription of SIAH1 is up-regulated in non-tumorigenic clonal populations of cells derived from 2 different tumorigenic parental cell lines [12].
  • These data suggest that Siah-1 is part of a novel regulatory loop controlling the level of OBF-1 protein in B cells [8].
  • Synphilin-1 and Siah-1 proteins were endogenously expressed in the central nervous system and were found to coimmunoprecipitate each other in rat brain homogenate [14].

Associations of SIAH1 with chemical compounds


Physical interactions of SIAH1

  • Inability of the proteasome to degrade synphilin-1/SIAH complex leads to a robust formation of ubiquitylated cytosolic inclusions [1].
  • We show that TIEG1 and SIAH1 interact through an amino-terminal domain of TIEG1 [19].
  • SIAH-1 interacts with CtIP and promotes its degradation by the proteasome pathway [11].
  • Association with PML requires the substrate-binding domain (SBD) of SIAH-1/2 through an interacting surface apparently distinct from those predicted by the structural studies, or shown experimentally to mediate binding to SIAH-associated factors [20].
  • A mutant Siah protein lacking the amino-terminal Ubc-binding sequences complexed with DCC, but did not degrade it [6].

Enzymatic interactions of SIAH1

  • DCC was found to be ubiquitinated and the Sina/Siah proteins regulated its expression [6].

Regulatory relationships of SIAH1

  • GSK3beta decreased the in vitro and in vivo ubiquitylation of synphilin-1 as well as its degradation promoted by SIAH [13].
  • Thus, Siah-1L represents a new member of the human Siah family that is induced in response to p53 and plays an important role in the regulation of beta-catenin activity in tumor cells [21].
  • The RING finger protein Siah-1 regulates the level of the transcriptional coactivator OBF-1 [8].
  • We show that inhibition of endogenous Siah-1 stabilizes and activates beta-catenin in B cells [4].

Other interactions of SIAH1

  • SIAH1 and SIAH2 are known regulators of protein stability [22].
  • SIAH proteins ubiquitylate synphilin-1 both in vitro and in vivo, promoting its degradation by the ubiquitin-proteasome system [1].
  • Involvement of PEG10 in human hepatocellular carcinogenesis through interaction with SIAH1 [23].
  • In this study, we have investigated the functional significance of p53-inducible human Siah-family protein expression in the regulation of beta-catenin activity [21].
  • In this report, we describe the identification of an E3 ubiquitin ligase, Seven in Absentia homologue-1 (SIAH1), as a TIEG1-interacting protein [19].

Analytical, diagnostic and therapeutic context of SIAH1


  1. Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson's disease. Liani, E., Eyal, A., Avraham, E., Shemer, R., Szargel, R., Berg, D., Bornemann, A., Riess, O., Ross, C.A., Rott, R., Engelender, S. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  2. SIAH1 inactivation correlates with tumor progression in hepatocellular carcinomas. Matsuo, K., Satoh, S., Okabe, H., Nomura, A., Maeda, T., Yamaoka, Y., Ikai, I. Genes Chromosomes Cancer (2003) [Pubmed]
  3. Siah proteins, HIF prolyl hydroxylases, and the physiological response to hypoxia. Simon, M.C. Cell (2004) [Pubmed]
  4. Up-regulation of beta-catenin by a viral oncogene correlates with inhibition of the seven in absentia homolog 1 in B lymphoma cells. Jang, K.L., Shackelford, J., Seo, S.Y., Pagano, J.S. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  5. Siah-1 N-terminal RING domain is required for proteolysis function, and C-terminal sequences regulate oligomerization and binding to target proteins. Hu, G., Fearon, E.R. Mol. Cell. Biol. (1999) [Pubmed]
  6. Mammalian homologs of seven in absentia regulate DCC via the ubiquitin-proteasome pathway. Hu, G., Zhang, S., Vidal, M., Baer, J.L., Xu, T., Fearon, E.R. Genes Dev. (1997) [Pubmed]
  7. Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein. Liu, J., Stevens, J., Rote, C.A., Yost, H.J., Hu, Y., Neufeld, K.L., White, R.L., Matsunami, N. Mol. Cell (2001) [Pubmed]
  8. The RING finger protein Siah-1 regulates the level of the transcriptional coactivator OBF-1. Tiedt, R., Bartholdy, B.A., Matthias, G., Newell, J.W., Matthias, P. EMBO J. (2001) [Pubmed]
  9. SIAH1 targets the alternative splicing factor T-STAR for degradation by the proteasome. Venables, J.P., Dalgliesh, C., Paronetto, M.P., Skitt, L., Thornton, J.K., Saunders, P.T., Sette, C., Jones, K.T., Elliott, D.J. Hum. Mol. Genet. (2004) [Pubmed]
  10. Characterization of human homologs of the Drosophila seven in absentia (sina) gene. Hu, G., Chung, Y.L., Glover, T., Valentine, V., Look, A.T., Fearon, E.R. Genomics (1997) [Pubmed]
  11. SIAH-1 interacts with CtIP and promotes its degradation by the proteasome pathway. Germani, A., Prabel, A., Mourah, S., Podgorniak, M.P., Di Carlo, A., Ehrlich, R., Gisselbrecht, S., Varin-Blank, N., Calvo, F., Bruzzoni-Giovanelli, H. Oncogene (2003) [Pubmed]
  12. Lack of somatic mutation in the coding sequence of SIAH1 in tumors hemizygous for this candidate tumor suppressor gene. Medhioub, M., Vaury, C., Hamelin, R., Thomas, G. Int. J. Cancer (2000) [Pubmed]
  13. Glycogen synthase kinase 3beta modulates synphilin-1 ubiquitylation and cellular inclusion formation by SIAH: implications for proteasomal function and Lewy body formation. Avraham, E., Szargel, R., Eyal, A., Rott, R., Engelender, S. J. Biol. Chem. (2005) [Pubmed]
  14. Siah-1 facilitates ubiquitination and degradation of synphilin-1. Nagano, Y., Yamashita, H., Takahashi, T., Kishida, S., Nakamura, T., Iseki, E., Hattori, N., Mizuno, Y., Kikuchi, A., Matsumoto, M. J. Biol. Chem. (2003) [Pubmed]
  15. SIAH1 causes growth arrest and apoptosis in hepatoma cells through beta-catenin degradation-dependent and -independent mechanisms. Yoshibayashi, H., Okabe, H., Satoh, S., Hida, K., Kawashima, K., Hamasu, S., Nomura, A., Hasegawa, S., Ikai, I., Sakai, Y. Oncol. Rep. (2007) [Pubmed]
  16. Regulation of 2-oxoglutarate (alpha-ketoglutarate) dehydrogenase stability by the RING finger ubiquitin ligase Siah. Habelhah, H., Laine, A., Erdjument-Bromage, H., Tempst, P., Gershwin, M.E., Bowtell, D.D., Ronai, Z. J. Biol. Chem. (2004) [Pubmed]
  17. Inactivating mutations of the Siah-1 gene in gastric cancer. Kim, C.J., Cho, Y.G., Park, C.H., Jeong, S.W., Nam, S.W., Kim, S.Y., Lee, S.H., Yoo, N.J., Lee, J.Y., Park, W.S. Oncogene (2004) [Pubmed]
  18. Hexachlorophene inhibits Wnt/beta-catenin pathway by promoting Siah-mediated beta-catenin degradation. Park, S., Gwak, J., Cho, M., Song, T., Won, J., Kim, D.E., Shin, J.G., Oh, S. Mol. Pharmacol. (2006) [Pubmed]
  19. Modulation of transforming growth factor beta (TGFbeta)/Smad transcriptional responses through targeted degradation of TGFbeta-inducible early gene-1 by human seven in absentia homologue. Johnsen, S.A., Subramaniam, M., Monroe, D.G., Janknecht, R., Spelsberg, T.C. J. Biol. Chem. (2002) [Pubmed]
  20. The coiled-coil domain is the structural determinant for mammalian homologues of Drosophila Sina-mediated degradation of promyelocytic leukemia protein and other tripartite motif proteins by the proteasome. Fanelli, M., Fantozzi, A., De Luca, P., Caprodossi, S., Matsuzawa, S., Lazar, M.A., Pelicci, P.G., Minucci, S. J. Biol. Chem. (2004) [Pubmed]
  21. Siah-1L, a novel transcript variant belonging to the human Siah family of proteins, regulates beta-catenin activity in a p53-dependent manner. Iwai, A., Marusawa, H., Matsuzawa, S., Fukushima, T., Hijikata, M., Reed, J.C., Shimotohno, K., Chiba, T. Oncogene (2004) [Pubmed]
  22. Regulation of BOB.1/OBF.1 stability by SIAH. Boehm, J., He, Y., Greiner, A., Staudt, L., Wirth, T. EMBO J. (2001) [Pubmed]
  23. Involvement of PEG10 in human hepatocellular carcinogenesis through interaction with SIAH1. Okabe, H., Satoh, S., Furukawa, Y., Kato, T., Hasegawa, S., Nakajima, Y., Yamaoka, Y., Nakamura, Y. Cancer Res. (2003) [Pubmed]
  24. Structural analysis of Siah1 and its interactions with Siah-interacting protein (SIP). Matsuzawa, S., Li, C., Ni, C.Z., Takayama, S., Reed, J.C., Ely, K.R. J. Biol. Chem. (2003) [Pubmed]
  25. Seven in absentia homolog 1A mediates ubiquitination and degradation of group 1 metabotropic glutamate receptors. Moriyoshi, K., Iijima, K., Fujii, H., Ito, H., Cho, Y., Nakanishi, S. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
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