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| | Domains of human Siah2 protein. |
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| Description | Human Siah2 protein consists of 324 amino acids, with a molecular weight of 36 KDa. Siah protein consists of an N-terminal ring domain, followed by two zinc finger motifs, and a C-terminal substrate binding domain (SBD). The ring domain is the catalytic domain that recruits E2 ubiquitin-conjugating enzymes, while the SBD mediates the binding of adaptor proteins or some Siah substrate proteins. The structure of murine Siah1a SBD has been solved. The structure reveals that Siah is a dimeric protein, and the SBD adopts an eight-stranded beta-sandwich fold (Polekhina et al., 2001). The substrate binding groove is formed by the beta-sandwich fold and the beta-strand that connects to the second zinc finger domain (House et al., 2005). |
| Expression | Siah2 mRNA is widely expressed in the embryonic and adult mouse tissues. It is expressed at a higher level in the olfactory epithelium, retina, forebrain and proliferating cartilage of developing bone (Della et al., 1993). Siah2 mRNA is also expressed in most human tissues (Hu et al., 1997). |
| Localisation | Siah protein can be localized in both cytoplasm and nucleus. |
| Function | Siah2 is the mammalian homolog of Drosophila SINA (seven in absentia), which interacts with transcriptional repressor Tramtrack via adaptor protein PHYL (Phyllopod) and induces the proteasomal degradation of Tramtrack, thereby determining R7 cell fate (Li et al., 1997; Tang et al., 1997). As a ring-finger E3 ubiquitin ligase, Siah targets the degradation of diverse substrates via ubiquitin-proteasome pathway, and affects multiple signaling pathways such as HIF (Nakayama et al., 2004), Ras (Nadeau et al., 2007; Schmidt et al., 2007), NF-kB (Polekhina et al., 2002; Habelhah et al., 2002), and beta-catenin (Liu et al., 2001; Matsuzawa and Reed, 2001). Siah2 transcription is upregulated by hypoxia (Nakayama et al., 2004); p38-mediated phosphorylation of mouse Siah2 on Thr24 and Ser29 alters its subcellular localization (Khurana et al., 2006); HIPK2-mediated phosphorylation of human Siah2 on Thr 26, Ser 28 and Ser 68 decreases the stability of Siah2 and impairs its interaction with HIPK2 (Calzado et al., 2009).
Over 20 Siah substrates have been reported (Nakayama et al., 2009) and some of them can be degradated by Siah2, Siah1 or both of them. In contrast to Siah1a knockout mice which exibit growth retardation and spermatogenesis defect, Siah2 knockout mice display no apparent phenotype, whereas Siah2 and Siah1a double knockout mice are embryonic or neonatal lethal, suggesting that the two Siah homologs have both overlapping and distinct functions in vivo (Frew et al., 2003). Despite the diverse substrates of Siah identified in vitro, loss of Siah2 (or both Siah2 and Siah1a) in vivo largely has no effect on the levels of many Siah substrates and the physiological processes associated with these substrates (Frew et al., 2002; Frew et al., 2003).
Siah2 is implicated in the regulation of hypoxia response through its effect on HIF prolyl hydroxylases or HIPK2 (Nakayama et al., 2004; Calzado et al., 2009). Siah2 knockout mice subject to hypoxia showed impaired respiratory response and defect to adjust levels of red blood cells (Nakayama et al., 2004). Siah2 has been shown to be required for development and progression of several types of cancers via its regulation of HIF or Ras pathways (House et al., 2009). Siah2-dependent degradation of Pard3A is found to control germinal zone exit of neuronal progenitors or immature neurons in mice (Famulski et al., 2010). |
| Homology | Homologs: Human has two Siah genes (Siah1 and Siah2) (Hu et al., 1997), while mouse has three Siah genes (Siah2, Siah1a, Siah1b) (Della et al., 1993). Human Siah2 shares 77% identity with human Siah1 (Hu et al., 1997).
Orthologs: Highly conserved Siah2 orthologs have been identified in all multicellular organisms examined (Nakayama et al., 2009). |
| Characterization of human homologs of the Drosophila seven in absentia (sina) gene. |
| Hu G, Chung YL, Glover T, Valentine V, Look AT, Fearon ER. |
| Genomics. 1997 Nov 15;46(1):103-11. |
| PMID 9403064 |
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| Photoreceptor cell differentiation requires regulated proteolysis of the transcriptional repressor Tramtrack. |
| Li S, Li Y, Carthew RW, Lai ZC. |
| Cell. 1997 Aug 8;90(3):469-78. |
| PMID 9267027 |
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| PHYL acts to down-regulate TTK88, a transcriptional repressor of neuronal cell fates, by a SINA-dependent mechanism. |
| Tang AH, Neufeld TP, Kwan E, Rubin GM. |
| Cell. 1997 Aug 8;90(3):459-67. |
| PMID 9267026 |
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| Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein. |
| Liu J, Stevens J, Rote CA, Yost HJ, Hu Y, Neufeld KL, White RL, Matsunami N. |
| Mol Cell. 2001 May;7(5):927-36. |
| PMID 11389840 |
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| Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin degradation linked to p53 responses. |
| Matsuzawa SI, Reed JC. |
| Mol Cell. 2001 May;7(5):915-26. |
| PMID 11389839 |
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| Normal p53 function in primary cells deficient for Siah genes. |
| Frew IJ, Dickins RA, Cuddihy AR, Del Rosario M, Reinhard C, O'Connell MJ, Bowtell DD. |
| Mol Cell Biol. 2002 Dec;22(23):8155-64. |
| PMID 12417719 |
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| Stress-induced decrease in TRAF2 stability is mediated by Siah2. |
| Habelhah H, Frew IJ, Laine A, Janes PW, Relaix F, Sassoon D, Bowtell DD, Ronai Z. |
| EMBO J. 2002 Nov 1;21(21):5756-65. |
| PMID 12411493 |
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| Siah ubiquitin ligase is structurally related to TRAF and modulates TNF-alpha signaling. |
| Polekhina G, House CM, Traficante N, Mackay JP, Relaix F, Sassoon DA, Parker MW, Bowtell DD. |
| Nat Struct Biol. 2002 Jan;9(1):68-75. |
| PMID 11742346 |
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| Generation and analysis of Siah2 mutant mice. |
| Frew IJ, Hammond VE, Dickins RA, Quinn JM, Walkley CR, Sims NA, Schnall R, Della NG, Holloway AJ, Digby MR, Janes PW, Tarlinton DM, Purton LE, Gillespie MT, Bowtell DD. |
| Mol Cell Biol. 2003 Dec;23(24):9150-61. |
| PMID 14645526 |
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| Siah2 regulates stability of prolyl-hydroxylases, controls HIF1alpha abundance, and modulates physiological responses to hypoxia. |
| Nakayama K, Frew IJ, Hagensen M, Skals M, Habelhah H, Bhoumik A, Kadoya T, Erdjument-Bromage H, Tempst P, Frappell PB, Bowtell DD, Ronai Z. |
| Cell. 2004 Jun 25;117(7):941-52. |
| PMID 15210114 |
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| Elucidation of the substrate binding site of Siah ubiquitin ligase. |
| House CM, Hancock NC, Moller A, Cromer BA, Fedorov V, Bowtell DD, Parker MW, Polekhina G. |
| Structure. 2006 Apr;14(4):695-701. |
| PMID 16615911 |
| |
| Regulation of the ring finger E3 ligase Siah2 by p38 MAPK. |
| Khurana A, Nakayama K, Williams S, Davis RJ, Mustelin T, Ronai Z. |
| J Biol Chem. 2006 Nov 17;281(46):35316-26. Epub 2006 Sep 25. |
| PMID 17003045 |
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| Regulation of Sprouty2 stability by mammalian Seven-in-Absentia homolog 2. |
| Nadeau RJ, Toher JL, Yang X, Kovalenko D, Friesel R. |
| J Cell Biochem. 2007 Jan 1;100(1):151-60. |
| PMID 16888801 |
| |
| Inhibition of RAS-mediated transformation and tumorigenesis by targeting the downstream E3 ubiquitin ligase seven in absentia homologue. |
| Schmidt RL, Park CH, Ahmed AU, Gundelach JH, Reed NR, Cheng S, Knudsen BE, Tang AH. |
| Cancer Res. 2007 Dec 15;67(24):11798-810. |
| PMID 18089810 |
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| Effect of disrupting seven-in-absentia homolog 2 function on lung cancer cell growth. |
| Ahmed AU, Schmidt RL, Park CH, Reed NR, Hesse SE, Thomas CF, Molina JR, Deschamps C, Yang P, Aubry MC, Tang AH. |
| J Natl Cancer Inst. 2008 Nov 19;100(22):1606-29. Epub 2008 Nov 11. |
| PMID 19001609 |
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| The ubiquitin ligase Siah2 regulates tumorigenesis and metastasis by HIF-dependent and -independent pathways. |
| Qi J, Nakayama K, Gaitonde S, Goydos JS, Krajewski S, Eroshkin A, Bar-Sagi D, Bowtell D, Ronai Z. |
| Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16713-8. Epub 2008 Oct 22. |
| PMID 18946040 |
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| Siah proteins: novel drug targets in the Ras and hypoxia pathways. |
| House CM, Moller A, Bowtell DD. |
| Cancer Res. 2009 Dec 1;69(23):8835-8. Epub 2009 Nov 17. (REVIEW) |
| PMID 19920190 |
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| An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response. |
| Calzado MA, de la Vega L, Moller A, Bowtell DD, Schmitz ML. |
| Nat Cell Biol. 2009 Jan;11(1):85-91. Epub 2008 Nov 30. |
| PMID 19043406 |
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| Inhibition of Siah ubiquitin ligase function. |
| Moller A, House CM, Wong CS, Scanlon DB, Liu MC, Ronai Z, Bowtell DD. |
| Oncogene. 2009 Jan 15;28(2):289-96. Epub 2008 Oct 13. |
| PMID 18850011 |
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| The ubiquitin ligase Siah2 and the hypoxia response. |
| Nakayama K, Qi J, Ronai Z. |
| Mol Cancer Res. 2009 Apr;7(4):443-51. (REVIEW) |
| PMID 19372575 |
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| Inhibition of Siah2 ubiquitin ligase by vitamin K3 (menadione) attenuates hypoxia and MAPK signaling and blocks melanoma tumorigenesis. |
| Shah M, Stebbins JL, Dewing A, Qi J, Pellecchia M, Ronai ZA. |
| Pigment Cell Melanoma Res. 2009 Dec;22(6):799-808. Epub 2009 Aug 27. |
| PMID 19712206 |
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| Increased SIAH expression predicts ductal carcinoma in situ (DCIS) progression to invasive carcinoma. |
| Behling KC, Tang A, Freydin B, Chervoneva I, Kadakia S, Schwartz GF, Rui H, Witkiewicz AK. |
| Breast Cancer Res Treat. 2010 Nov 19. [Epub ahead of print] |
| PMID 21088888 |
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| Siah regulation of Pard3A controls neuronal cell adhesion during germinal zone exit. |
| Famulski JK, Trivedi N, Howell D, Yang Y, Tong Y, Gilbertson R, Solecki DJ. |
| Science. 2010 Dec 24;330(6012):1834-8. Epub 2010 Nov 25. |
| PMID 21109632 |
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| Siah2-dependent concerted activity of HIF and FoxA2 regulates formation of neuroendocrine phenotype and neuroendocrine prostate tumors. |
| Qi J, Nakayama K, Cardiff RD, Borowsky AD, Kaul K, Williams R, Krajewski S, Mercola D, Carpenter PM, Bowtell D, Ronai ZA. |
| Cancer Cell. 2010 Jul 13;18(1):23-38. |
| PMID 20609350 |
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| Isolation and characterisation of murine homologues of the Drosophila seven in absentia gene (sina). |
| Della NG, Senior PV, Bowtell DD. |
| Oncotarget. 2010 Sep 24;1(5):379-385. |
| PMID 8404535 |
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