Cell Biochemistry and Biophysics

, Volume 67, Issue 1, pp 15–24 | Cite as

Regulators and Effectors of Siah Ubiquitin Ligases

  • Jianfei Qi
  • Hyungsoo Kim
  • Marzia Scortegagna
  • Ze’ev A. Ronai
Original Paper


The Siah ubiquitin ligases are members of the RING finger E3 ligases. The Siah E3s are conserved from fly to mammals. Primarily implicated in cellular stress responses, Siah ligases play a key role in hypoxia, through the regulation of HIF-1α transcription stability and activity. Concomitantly, physiological conditions associated with varying oxygen tension often highlight the importance of Siah, as seen in cancer and neurodegenerative disorders. Notably, recent studies also point to the role of these ligases in fundamental processes including DNA damage response, cellular organization and polarity. This review summarizes the current understanding of upstream regulators and downstream effectors of Siah.


Siah1 Siah2 Ubiquitin ligase Hypoxia Stress signaling DNA damage 



Support by NCI Grants CA099961 and CA128814 (to ZR) and CA154888 (to JQ) is gratefully acknowledged. We thank Allan Weisman and Serge Fuchs for the critical reading of this manuscript.


  1. 1.
    Hershko, A., & Ciechanover, A. (1998). The ubiquitin system. Annual Review of Biochemistry, 67, 425–479.CrossRefPubMedGoogle Scholar
  2. 2.
    Schnell, J. D., & Hicke, L. (2003). Non-traditional functions of ubiquitin and ubiquitin-binding proteins. Journal of Biological Chemistry, 278, 35857–35860.CrossRefPubMedGoogle Scholar
  3. 3.
    Reed, J. C., & Ely, K. R. (2002). Degrading liaisons: Siah structure revealed. Natural Structural Biology, 9, 8–10.CrossRefGoogle Scholar
  4. 4.
    Genbacev, O., Zhou, Y., Ludlow, J. W., & Fisher, S. J. (1997). Regulation of human placental development by oxygen tension. Science, 277, 1669–1672.CrossRefPubMedGoogle Scholar
  5. 5.
    Tang, A. H., Neufeld, T. P., Kwan, E., & Rubin, G. M. (1997). PHYL acts to down-regulate TTK88, a transcriptional repressor of neuronal cell fates, by a SINA-dependent mechanism. Cell, 90, 459–467.CrossRefPubMedGoogle Scholar
  6. 6.
    Della, N. G., Senior, P. V., & Bowtell, D. D. (1993). Isolation and characterisation of murine homologues of the Drosophila seven in absentia gene (sina). Development, 117, 1333–1343.PubMedGoogle Scholar
  7. 7.
    Matsuzawa, S. I., & Reed, J. C. (2001). Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin degradation linked to p53 responses. Molecular Cell, 7, 915–926.CrossRefPubMedGoogle Scholar
  8. 8.
    Li, S., Xu, C., & Carthew, R. W. (2002). Phyllopod acts as an adaptor protein to link the sina ubiquitin ligase to the substrate protein tramtrack. Molecular and Cellular Biology, 22, 6854–6865.CrossRefPubMedGoogle Scholar
  9. 9.
    Frew, I. J., Hammond, V. E., Dickins, R. A., Quinn, J. M., Walkley, C. R., Sims, N. A., et al. (2003). Generation and analysis of Siah2 mutant mice. Molecular and Cellular Biology, 23, 9150–9161.CrossRefPubMedGoogle Scholar
  10. 10.
    Liu, M., Hsu, J., Chan, C., Li, Z., & Zhou, Q. (2012). The ubiquitin ligase Siah1 controls ELL2 stability and formation of super elongation complexes to modulate gene transcription. Molecular Cell, 46, 325–334.CrossRefPubMedGoogle Scholar
  11. 11.
    Grishina, I., Debus, K., Garcia-Limones, C., Schneider, C., Shresta, A., Garcia, C., et al. (2012). SIAH-mediated ubiquitination and degradation of acetyl-transferases regulate the p53 response and protein acetylation. Biochimica et Biophysica Acta, 1823, 2287–2296.CrossRefPubMedGoogle Scholar
  12. 12.
    Kilroy, G., Kirk-Ballard, H., Carter, L. E., & Floyd, Z. E. (2012). The ubiquitin ligase Siah2 regulates PPARgamma activity in adipocytes. Endocrinology, 153, 1206–1218.CrossRefPubMedGoogle Scholar
  13. 13.
    Zhao, H. L., Ueki, N., & Hayman, M. J. (2010). The Ski protein negatively regulates Siah2-mediated HDAC3 degradation. Biochemical and Biophysical Research Communications, 399, 623–628.CrossRefPubMedGoogle Scholar
  14. 14.
    Wu, H., Lin, Y., Shi, Y., Qian, W., Tian, Z., Yu, Y., et al. (2010). SIAH-1 interacts with mammalian polyhomeotic homologues HPH2 and affects its stability via the ubiquitin-proteasome pathway. Biochemical and Biophysical Research Communications, 397, 391–396.CrossRefPubMedGoogle Scholar
  15. 15.
    Calzado, M. A., de la Vega, L., Moller, A., Bowtell, D. D., & Schmitz, M. L. (2009). An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response. Nature Cell Biology, 11, 85–91.CrossRefPubMedGoogle Scholar
  16. 16.
    Winter, M., Sombroek, D., Dauth, I., Moehlenbrink, J., Scheuermann, K., Crone, J., et al. (2008). Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR. Nature Cell Biology, 10, 812–824.CrossRefPubMedGoogle Scholar
  17. 17.
    Buchwald, M., Pietschmann, K., Brand, P., Gunther, A., Mahajan, NP., Heinze,l T., and Kramer OH (2012) SIAH ubiquitin ligases target the nonreceptor tyrosine kinase ACK1 for ubiquitinylation and proteasomal degradation. Oncogene. 2012.Google Scholar
  18. 18.
    Zhou, Y., Li, L., Liu, Q., Xing, G., Kuai, X., Sun, J., et al. (2008). E3 ubiquitin ligase SIAH1 mediates ubiquitination and degradation of TRB3. Cellular Signalling, 20, 942–948.CrossRefPubMedGoogle Scholar
  19. 19.
    Yun, S., Moller, A., Chae, S. K., Hong, W. P., Bae, Y. J., Bowtell, D. D., et al. (2008). Siah proteins induce the epidermal growth factor-dependent degradation of phospholipase Cepsilon. Journal of Biological Chemistry, 283, 1034–1042.CrossRefPubMedGoogle Scholar
  20. 20.
    Nadeau, R. J., Toher, J. L., Kovalenko, D., & Friesel, R. (2007). Regulation of Sprouty2 stability by mammalian Seven-in-Absentia homolog 2. Journal of Cellular Biochemistry, 100, 151–160.CrossRefPubMedGoogle Scholar
  21. 21.
    Famulski, J. K., Trivedi, N., Howell, D., Yang, Y., Tong, Y., Gilbertson, R., et al. (2010). Siah regulation of Pard3A controls neuronal cell adhesion during germinal zone exit. Science, 330, 1834–1838.CrossRefPubMedGoogle Scholar
  22. 22.
    Nagano, Y., Fukushima, T., Okemoto, K., Tanaka, K., Bowtell, D. D., Ronai, Z., et al. (2011). Siah1/SIP regulates p27(kip1) stability and cell migration under metabolic stress. Cell Cycle, 10, 2592–2602.CrossRefPubMedGoogle Scholar
  23. 23.
    Bhanot, M., & Smith, S. (2012). TIN2 stability is regulated by the E3 ligase Siah2. Molecular and Cellular Biology, 32, 376–384.CrossRefPubMedGoogle Scholar
  24. 24.
    Sarkar, T. R., Sharan, S., Wang, J., Pawar, S. A., Cantwell, C. A., Johnson, P. F., et al. (2012). Identification of a Src tyrosine kinase/SIAH2 E3 ubiquitin ligase pathway that regulates C/EBPdelta expression and contributes to transformation of breast tumor cells. Molecular and Cellular Biology, 32, 320–332.CrossRefPubMedGoogle Scholar
  25. 25.
    Zhao, J., Wang, C., Wang, J., Yang, X., Diao, N., Li, Q., et al. (2011). E3 ubiquitin ligase Siah-1 facilitates poly-ubiquitylation and proteasomal degradation of the hepatitis B viral X protein. FEBS Letters, 585, 2943–2950.CrossRefPubMedGoogle Scholar
  26. 26.
    Wu, H., Shi, Y., Lin, Y., Qian, W., Yu, Y., & Huo, K. (2011). Eukaryotic translation elongation factor 1 delta inhibits the ubiquitin ligase activity of SIAH-1. Molecular and Cellular Biochemistry, 357, 209–215.CrossRefPubMedGoogle Scholar
  27. 27.
    Scortegagna, M., Subtil, T., Qi, J., Kim, H., Zhao, W., Gu, W., et al. (2011). USP13 enzyme regulates Siah2 ligase stability and activity via noncatalytic ubiquitin-binding domains. Journal of Biological Chemistry, 286, 27333–27341.CrossRefPubMedGoogle Scholar
  28. 28.
    Nagel, C. H., Albrecht, N., Milovic-Holm, K., Mariyanna, L., Keyser, B., Abel, B., et al. (2011). Herpes simplex virus immediate-early protein ICP0 is targeted by SIAH-1 for proteasomal degradation. Journal of Virology, 85, 7644–7657.CrossRefPubMedGoogle Scholar
  29. 29.
    Garrison, J. B., Correa, R. G., Gerlic, M., Yip, K. W., Krieg, A., Tamble, C. M., et al. (2011). ARTS and Siah collaborate in a pathway for XIAP degradation. Molecular Cell, 41, 107–116.CrossRefPubMedGoogle Scholar
  30. 30.
    Twomey, E., Li, Y., Lei, J., Sodja, C., Ribecco-Lutkiewicz, M., Smith, B., et al. (2010). Regulation of MYPT1 stability by the E3 ubiquitin ligase SIAH2. Experimental Cell Research, 316, 68–77.CrossRefPubMedGoogle Scholar
  31. 31.
    Ban, R., Matsuzaki, H., Akashi, T., Sakashita, G., Taniguchi, H., Park, S. Y., et al. (2009). Mitotic regulation of the stability of microtubule plus-end tracking protein EB3 by ubiquitin ligase SIAH-1 and Aurora mitotic kinases. Journal of Biological Chemistry, 284, 28367–28381.CrossRefPubMedGoogle Scholar
  32. 32.
    Kim, H., Scimia, M. C., Wilkinson, D., Trelles, R. D., Wood, M. R., Bowtell, D., et al. (2011). Fine-tuning of Drp1/Fis1 availability by AKAP121/Siah2 regulates mitochondrial adaptation to hypoxia. Molecular Cell, 44, 532–544.CrossRefPubMedGoogle Scholar
  33. 33.
    Carlucci, A., Adornetto, A., Scorziello, A., Viggiano, D., Foca, M., Cuomo, O., et al. (2008). Proteolysis of AKAP121 regulates mitochondrial activity during cellular hypoxia and brain ischaemia. EMBO Journal, 27, 1073–1084.CrossRefPubMedGoogle Scholar
  34. 34.
    Szczepanowski, M., Adam-Klages, S., Kruse, M. L., Pollmann, M., Klapper, W., Parwaresch, R., et al. (2007). Regulation of repp 86 stability by human Siah2. Biochemical and Biophysical Research Communications, 362, 485–490.CrossRefPubMedGoogle Scholar
  35. 35.
    Nakayama, K., Frew, I. J., Hagensen, M., Skals, M., Habelhah, H., Bhoumik, A., et al. (2004). Siah2 regulates stability of prolyl-hydroxylases, controls HIF1alpha abundance, and modulates physiological responses to hypoxia. Cell, 117, 941–952.CrossRefPubMedGoogle Scholar
  36. 36.
    Yego, E. C., & Mohr, S. (2010). Siah-1 protein is necessary for high glucose-induced glyceraldehyde-3-phosphate dehydrogenase nuclear accumulation and cell death in Muller cells. Journal of Biological Chemistry, 2010(285), 3181–3190.CrossRefGoogle Scholar
  37. 37.
    Fiucci, G., Beaucourt, S., Duflaut, D., Lespagnol, A., Stumptner-Cuvelette, P., Geant, A., et al. (2004). Siah-1b is a direct transcriptional target of p53: identification of the functional p53 responsive element in the siah-1b promoter. Proc Natl Acad Sci U S A., 101, 3510–3515.CrossRefPubMedGoogle Scholar
  38. 38.
    Qi, J., Nakayama, K., Gaitonde, S., Goydos, J. S., Krajewski, S., Eroshkin, A., et al. (2008). The ubiquitin ligase Siah2 regulates tumorigenesis and metastasis by HIF-dependent and -independent pathways. Proc Natl Acad Sci USA, 105, 16713–16718.CrossRefPubMedGoogle Scholar
  39. 39.
    Qi, J., Nakayama, K., Cardiff, R. D., Borowsky, A. D., Kaul, K., Williams, R., et al. (2010). Siah2-dependent concerted activity of HIF and FoxA2 regulates formation of neuroendocrine phenotype and neuroendocrine prostate tumors. Cancer Cell, 18, 23–38.CrossRefPubMedGoogle Scholar
  40. 40.
    Chan, P., Moller, A., Liu, M. C., Sceneay, J. E., Wong, C. S., Waddell, N., et al. (2011). The expression of the ubiquitin ligase SIAH2 (seven in absentia homolog 2) is mediated through gene copy number in breast cancer and is associated with a basal-like phenotype and p53 expression. Breast Cancer Research, 13, R19.CrossRefPubMedGoogle Scholar
  41. 41.
    Ahmed, A. U., Schmidt, R. L., Park, C. H., Reed, N. R., Hesse, S. E., Thomas, C. F., et al. (2008). Effect of disrupting seven-in-absentia homolog 2 function on lung cancer cell growth. Journal of the National Cancer Institute, 100, 1606–1629.CrossRefPubMedGoogle Scholar
  42. 42.
    Schmidt, R. L., Park, C. H., Ahmed, A. U., Gundelach, J. H., Reed, N. R., Cheng, S., et al. (2007). Inhibition of RAS-mediated transformation and tumorigenesis by targeting the downstream E3 ubiquitin ligase seven in absentia homologue. Cancer Research, 67, 11798–11810.CrossRefPubMedGoogle Scholar
  43. 43.
    Brauckhoff, A., Malz, M., Tschaharganeh, D., Malek, N., Weber, A., Riener, M. O., et al. (2011). Nuclear expression of the ubiquitin ligase seven in absentia homolog (SIAH)-1 induces proliferation and migration of liver cancer cells. Journal of Hepatology, 55, 1049–1057.CrossRefPubMedGoogle Scholar
  44. 44.
    Malz, M., Aulmann, A., Samarin, J., Bissinger, M., Longerich, T., Schmitt, S., et al. (2012). Nuclear accumulation of seven in absentia homologue-2 supports motility and proliferation of liver cancer cells. International Journal of Cancer, 131, 2016–2026.CrossRefGoogle Scholar
  45. 45.
    Frasor, J., Danes, J. M., Funk, C. C., & Katzenellenbogen, B. S. (2005). Estrogen down-regulation of the corepressor N-CoR: mechanism and implications for estrogen derepression of N-CoR-regulated genes. Proc Natl Acad Sci USA, 102, 13153–13157.CrossRefPubMedGoogle Scholar
  46. 46.
    Maeda, A., Yoshida, T., Kusuzaki, K., & Sakai, T. (2002). The characterization of the human Siah-1 promoter(1). FEBS Letters, 512, 223–226.CrossRefPubMedGoogle Scholar
  47. 47.
    Topol, L., Jiang, X., Choi, H., Garrett-Beal, L., Carolan, P. J., & Yang, Y. (2003). Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3-independent beta-catenin degradation. Journal of Cell Biology, 162, 899–908.CrossRefPubMedGoogle Scholar
  48. 48.
    Xie, W., Mei, Y., & Wu, M. (2009). E2F1 represses beta-catenin/TCF activity by direct up-regulation of Siah1. Journal of Cellular and Molecular Medicine, 13, 1719–1727.CrossRefPubMedGoogle Scholar
  49. 49.
    MacLeod, R. J., Hayes, M., & Pacheco, I. (2007). Wnt5a secretion stimulated by the extracellular calcium-sensing receptor inhibits defective Wnt signaling in colon cancer cells. American Journal of Gastrointestinal and Liver Physiology, 293, G403–G411.CrossRefGoogle Scholar
  50. 50.
    Xu, Z., Sproul, A., Wang, W., Kukekov, N., & Greene, L. A. (2006). Siah1 interacts with the scaffold protein POSH to promote JNK activation and apoptosis. Journal of Biological Chemistry, 281, 303–312.CrossRefPubMedGoogle Scholar
  51. 51.
    Khurana, A., Nakayama, K., Williams, S., Davis, R. J., Mustelin, T., & Ronai, Z. (2006). Regulation of the ring finger E3 ligase Siah2 by p38 MAPK. Journal of Biological Chemistry, 281, 35316–35326.CrossRefPubMedGoogle Scholar
  52. 52.
    Perez, M., Garcia-Limones, C., Zapico, I., Marina, A., Schmitz, M. L., Munoz, E., et al. (2012). Mutual regulation between SIAH2 and DYRK2 controls hypoxic and genotoxic signaling pathways. J Mol Cell Biol, 4, 316–330.CrossRefPubMedGoogle Scholar
  53. 53.
    Shah, M., Stebbins, J. L., Dewing, A., Qi, J., Pellecchia, M., & Ronai, Z. A. (2009). Inhibition of Siah2 ubiquitin ligase by vitamin K3 (menadione) attenuates hypoxia and MAPK signaling and blocks melanoma tumorigenesis. Pigment Cell Melanoma Res, 22, 799–808.CrossRefPubMedGoogle Scholar
  54. 54.
    Le Moan, N., Houslay, D. M., Christian, F., Houslay, M. D., & Akassoglou, K. (2011). Oxygen-dependent cleavage of the p75 neurotrophin receptor triggers stabilization of HIF-1alpha. Molecular Cell, 44, 476–490.CrossRefPubMedGoogle Scholar
  55. 55.
    Liao Y, Zhang M and Lonnerdal B (2012) Growth factor TGF-beta induces intestinal epithelial cell (IEC-6) differentiation: miR-146b as a regulatory component in the negative feedback loop. Genes Nutr. 2012.Google Scholar
  56. 56.
    Imig, J., Motsch, N., Zhu, J. Y., Barth, S., Okoniewski, M., Reineke, T., et al. (2011). microRNA profiling in Epstein-Barr virus-associated B-cell lymphoma. Nucleic Acids Research, 39, 1880–1893.CrossRefPubMedGoogle Scholar
  57. 57.
    Pang, R. T., Liu, W. M., Leung, C. O., Ye, T. M., Kwan, P. C., Lee, K. F., et al. (2011). miR-135A regulates preimplantation embryo development through down-regulation of E3 Ubiquitin Ligase Seven In Absentia Homolog 1A (SIAH1A) expression. PLoS ONE, 6, e27878.CrossRefPubMedGoogle Scholar
  58. 58.
    Tofaris, G. K., Razzaq, A., Ghetti, B., Lilley, K. S., & Spillantini, M. G. (2003). Ubiquitination of alpha-synuclein in Lewy bodies is a pathological event not associated with impairment of proteasome function. Journal of Biological Chemistry, 278, 44405–44411.CrossRefPubMedGoogle Scholar
  59. 59.
    Liani, E., Eyal, A., Avraham, E., Shemer, R., Szargel, R., Berg, D., et al. (2004). 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. Proc Natl Acad Sci USA, 101, 5500–5505.CrossRefPubMedGoogle Scholar
  60. 60.
    Anderson, J. P., Walker, D. E., Goldstein, J. M., de Laat, R., Banducci, K., Caccavello, R. J., et al. (2006). Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. Journal of Biological Chemistry, 281, 29739–29752.CrossRefPubMedGoogle Scholar
  61. 61.
    Lee, J. T., Wheeler, T. C., Li, L., & Chin, L. S. (2008). Ubiquitination of alpha-synuclein by Siah-1 promotes alpha-synuclein aggregation and apoptotic cell death. Human Molecular Genetics, 17, 906–917.CrossRefPubMedGoogle Scholar
  62. 62.
    Engelender, S., Kaminsky, Z., Guo, X., Sharp, A. H., Amaravi, R. K., Kleiderlein, J. J., et al. (1999). Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions. Nature Genetics, 22, 110–114.CrossRefPubMedGoogle Scholar
  63. 63.
    Nagano, Y., Yamashita, H., Takahashi, T., Kishida, S., Nakamura, T., Iseki, E., et al. (2003). Siah-1 facilitates ubiquitination and degradation of synphilin-1. Journal of Biological Chemistry, 278, 51504–51514.CrossRefPubMedGoogle Scholar
  64. 64.
    Eyal, A., Szargel, R., Avraham, E., Liani, E., Haskin, J., Rott, R., et al. (2006). Synphilin-1A: an aggregation-prone isoform of synphilin-1 that causes neuronal death and is present in aggregates from alpha-synucleinopathy patients. Proc Natl Acad Sci USA, 103, 5917–5922.CrossRefPubMedGoogle Scholar
  65. 65.
    Szargel, R., Rott, R., Eyal, A., Haskin, J., Shani, V., Balan, L., et al. (2009). Synphilin-1A inhibits seven in absentia homolog (SIAH) and modulates alpha-synuclein monoubiquitylation and inclusion formation. Journal of Biological Chemistry, 284, 11706–11716.CrossRefPubMedGoogle Scholar
  66. 66.
    Fukuba, H., Takahashi, T., Jin, H. G., Kohriyama, T., & Matsumoto, M. (2008). Abundance of aspargynyl-hydroxylase FIH is regulated by Siah-1 under normoxic conditions. Neuroscience Letters, 433, 209–214.CrossRefPubMedGoogle Scholar
  67. 67.
    Calzado, M. A., de la Vega, L., Munoz, E., & Schmitz, M. L. (2009). Autoregulatory control of the p53 response by Siah-1L-mediated HIPK2 degradation. Biological Chemistry, 390, 1079–1083.CrossRefPubMedGoogle Scholar
  68. 68.
    Merrill, R. A., Dagda, R. K., Dickey, A. S., Cribbs, J. T., Green, S. H., Usachev, Y. M., et al. (2011). Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1. PLoS Biology, 9, e1000612.CrossRefPubMedGoogle Scholar
  69. 69.
    Ong, S. B., Subrayan, S., Lim, S. Y., Yellon, D. M., Davidson, S. M., & Hausenloy, D. J. (2010). Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation, 121, 2012–2022.CrossRefPubMedGoogle Scholar
  70. 70.
    D’Orazi, G., Cecchinelli, B., Bruno, T., Manni, I., Higashimoto, Y., Saito, S., et al. (2002). Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis. Nature Cell Biology, 4, 11–19.CrossRefPubMedGoogle Scholar
  71. 71.
    Hofmann, T. G., Moller, A., Sirma, H., Zentgraf, H., Taya, Y., Droge, W., et al. (2002). Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2. Nature Cell Biology, 4, 1–10.CrossRefPubMedGoogle Scholar
  72. 72.
    Zhang, Q., Yoshimatsu, Y., Hildebrand, J., Frisch, S. M., & Goodman, R. H. (2003). Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP. Cell, 115, 177–186.CrossRefPubMedGoogle Scholar
  73. 73.
    Longhese, M. P., Anbalagan, S., Martina, M., & Bonetti, D. (2012). The role of shelterin in maintaining telomere integrity. Frontiers in Bioscience, 17, 1715–1728.CrossRefGoogle Scholar
  74. 74.
    Fujita, K., Horikawa, I., Mondal, A. M., Jenkins, L. M., Appella, E., Vojtesek, B., et al. (2010). Positive feedback between p53 and TRF2 during telomere-damage signalling and cellular senescence. Nature Cell Biology, 12, 1205–1212.CrossRefPubMedGoogle Scholar
  75. 75.
    Karlseder, J., Smogorzewska, A., & de Lange, T. (2002). Senescence induced by altered telomere state, not telomere loss. Science, 295, 2446–2449.CrossRefPubMedGoogle Scholar
  76. 76.
    Liu, D., Safari, A., O’Connor, M. S., Chan, D. W., Laegeler, A., Qin, J., et al. (2004). PTOP interacts with POT1 and regulates its localization to telomeres. Nature Cell Biology, 6, 673–680.CrossRefPubMedGoogle Scholar
  77. 77.
    Wong, C. S., Sceneay, J., House, C. M., Halse, H. M., Liu, M. C., George, J., et al. (2012). Vascular normalization by loss of Siah2 results in increased chemotherapeutic efficacy. Cancer Research, 72, 1694–1704.CrossRefPubMedGoogle Scholar
  78. 78.
    Moller, A., House, C. M., Wong, C. S., Scanlon, D. B., Liu, M. C., Ronai, Z., et al. (2009). Inhibition of Siah ubiquitin ligase function. Oncogene, 28, 289–296.CrossRefPubMedGoogle Scholar
  79. 79.
    Liao, D., Corle, C., Seagroves, T. N., & Johnson, R. S. (2007). Hypoxia-inducible factor-1alpha is a key regulator of metastasis in a transgenic model of cancer initiation and progression. Cancer Research, 67, 563–572.CrossRefPubMedGoogle Scholar
  80. 80.
    Matsuo, K., Satoh, S., Okabe, H., Nomura, A., Maeda, T., Yamaoka, Y., et al. (2003). SIAH1 inactivation correlates with tumor progression in hepatocellular carcinomas. Genes, Chromosomes & Cancer, 36, 283–291.CrossRefGoogle Scholar
  81. 81.
    Kim, C. J., Cho, Y. G., Park, C. H., Jeong, S. W., Nam, S. W., Kim, S. Y., et al. (2004). Inactivating mutations of the Siah-1 gene in gastric cancer. Oncogene, 23, 8591–8596.CrossRefPubMedGoogle Scholar
  82. 82.
    Wen, Y. Y., Yang, Z. Q., Song, M., Li, B. L., Yao, X. H., Chen, X. L., et al. (2010). The expression of SIAH1 is downregulated and associated with Bim and apoptosis in human breast cancer tissues and cells. Molecular Carcinogenesis, 49, 440–449.PubMedGoogle Scholar
  83. 83.
    Wen, Y. Y., Yang, Z. Q., Song, M., Li, B. L., Zhu, J. J., & Wang, E. H. (2010). SIAH1 induced apoptosis by activation of the JNK pathway and inhibited invasion by inactivation of the ERK pathway in breast cancer cells. Cancer Science, 101, 73–79.CrossRefPubMedGoogle Scholar
  84. 84.
    He, H. T., Fokas, E., You, A., Engenhart-Cabillic, R., & An, H. X. (2010). Siah1 proteins enhance radiosensitivity of human breast cancer cells. BMC Cancer, 10, 403.CrossRefPubMedGoogle Scholar
  85. 85.
    Kramer, O. H., Muller, S., Buchwald, M., Reichardt, S., & Heinzel, T. (2008). Mechanism for ubiquitylation of the leukemia fusion proteins AML1-ETO and PML-RARalpha. FASEB J., 22, 1369–1379.CrossRefPubMedGoogle Scholar
  86. 86.
    Fanelli, M., Fantozzi, A., De Luca, P., Caprodossi, S., Matsuzawa, S., Lazar, M. A., et al. (2004). 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. Journal of Biological Chemistry, 279, 5374–5379.CrossRefPubMedGoogle Scholar
  87. 87.
    Bursen, A., Moritz, S., Gaussmann, A., Moritz, S., Dingermann, T., & Marschalek, R. (2004). Interaction of AF4 wild-type and AF4.MLL fusion protein with SIAH proteins: indication for t(4;11) pathobiology? Oncogene, 23, 6237–6249.CrossRefPubMedGoogle Scholar
  88. 88.
    Buchwald, M., Pietschmann, K., Muller, J. P., Bohmer, F. D., Heinzel, T., & Kramer, O. H. (2010). Ubiquitin conjugase UBCH8 targets active FMS-like tyrosine kinase 3 for proteasomal degradation. Leukemia, 24, 1412–1421.CrossRefPubMedGoogle Scholar
  89. 89.
    Qi, J., Pellecchia, M., & Ronai, Z. A. (2010). The Siah2-HIF-FoxA2 axis in prostate cancer—new markers and therapeutic opportunities. Oncotarget, 5, 379–385.Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Jianfei Qi
    • 1
  • Hyungsoo Kim
    • 1
  • Marzia Scortegagna
    • 1
  • Ze’ev A. Ronai
    • 1
  1. 1.Signal Transduction ProgramCancer Center, Sanford-Burnham Medical Research InstituteLa JollaUSA

Personalised recommendations