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Gene Review

SETD2  -  SET domain containing 2

Homo sapiens

Synonyms: FLJ23184, HBP231, HIF-1, HIF1, HIP-1, ...
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Disease relevance of SETD2

  • HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus [1].
  • BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates gene expression in critical pathways involved in tumor growth and metastases [2].
  • Studies of colitis in these mice revealed that decreased HIF-1 expression correlated with more severe clinical symptoms (mortality, weight loss, colon length), while increased HIF levels were protective in these parameters [3].
  • Taken together, these studies provide insight into tissue microenvironmental changes during model inflammatory bowel disease and identify HIF-1 as a critical factor for barrier protection during mucosal insult [3].
  • In addition to the HIF-1 complex, hepatocyte nuclear factor 4alpha (HNF4alpha) was found to be indispensable for hypoxia-induced EPO gene expression in hepatoma cells [4].

Psychiatry related information on SETD2

  • Considering that activation of HIF-1 provokes pro-survival as well as pro-death decisions under hypoxia, it will be crucial to understand decision making processes in regulating cell death, adaptation and chemoresistance [5].
  • In conclusion, these data clearly demonstrate that physical activity induces the HIF-1-mediated signaling pathway in human skeletal muscle, providing the first evidence that human HIF-1alpha can be activated during physiologically relevant conditions [6].

High impact information on SETD2


Chemical compound and disease context of SETD2


Biological context of SETD2

  • Thus, our results suggest that HYPB HMTase may coordinate histone methylation and transcriptional regulation in mammals and open perspective for the further study of the potential roles of HYPB protein in hematopoiesis and pathogenesis of HD [16].
  • In this report we describe how this hypoxic environment can be used to activate heterologous gene expression driven by a hypoxia-responsive element (HRE), which interacts with the transcriptional complex hypoxia-inducible factor-1 (HIF-1) [17].
  • Hypoxia-inducible factor-1 (HIF-1) has a key role in cellular responses to hypoxia, including the regulation of genes involved in energy metabolism, angiogenesis and apoptosis [9].
  • Thus, constitutive HIF-1 activation may underlie the angiogenic phenotype of VHL-associated tumours [9].
  • Here we demonstrate a critical role for the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL in HIF-1 regulation [9].

Anatomical context of SETD2


Associations of SETD2 with chemical compounds


Physical interactions of SETD2

  • Identification of the full-length huntingtin- interacting protein p231HBP/HYPB as a DNA-binding factor [26].
  • The hypoxia-inducible factor-1 (HIF-1) binding site located at approximately -1 kbp in the VEGF promoter was not required for down-regulation of promoter activity by gefitinib under normoxia [27].
  • Chromatin immunoprecipitation (ChIP) and sequential ChIP (re-ChIP) analysis showed that both Brm and Brg-1 associate with the enhancer region of the EPO gene in vivo in a hypoxia-dependent fashion and that each is present in a complex with HIF-1 [28].
  • Our data show that extracellular acidosis increased the level of CA IX protein, mRNA and the activity of minimal CA9 promoter that contains binding sites for HIF-1 and SP-1 transcription factors [29].
  • Expression of hypoxia-responsive genes is mediated by the heterodimeric transcription factor hypoxia-inducible factor-1 (HIF-1) in complex with the p300/CREB-binding protein (p300/CBP) transcriptional coactivator [30].

Enzymatic interactions of SETD2

  • Hypoxia-inducible factor 1 (HIF-1) is a phosphorylated protein and its phosphorylation is involved in HIF-1alpha subunit stabilization as well as in the regulation of HIF-1 transcriptional activity [31].

Regulatory relationships of SETD2


Other interactions of SETD2

  • Here we report the structural and functional characterization of the huntingtin interacting protein B (HYPB) [16].
  • 3) Coimmunoprecipitation assays indicate that HYPB protein associates with hyperphosphorylated RNA polymerase II (RNAPII) but not the unphosphorylated form [16].
  • Interestingly, PHD2 is upregulated by hypoxia, providing an HIF-1-dependent auto-regulatory mechanism driven by the oxygen tension [36].
  • The protein CITED2, which binds p300/CBP, is thought to be a negative regulator of HIF-1 transactivation [30].
  • Proteasomal inhibition attenuates transcriptional activity of hypoxia-inducible factor 1 (HIF-1) via specific effect on the HIF-1alpha C-terminal activation domain [37].

Analytical, diagnostic and therapeutic context of SETD2

  • Its expression, which is regulated by the HIF-1 transcription factor, is strongly induced by hypoxia and correlates with a poor response to classical chemo- and radiotherapies [38].
  • Western blot analysis revealed that the amount of the beta subunit of HIF-1, identical to aryl hydrocarbon receptor nuclear translocator 1 (ARNT1), and the homolog ARNT2 increased in nuclear extracts from SH-SY5Y cells exposed to anoxia [4].
  • In electrophoretic mobility shift assays, affinity-purified IgY antibody was shown to recognize the native HIF-1 (but not the related HIF-2) complex that specifically binds an oligonucleotide containing the HIF-1 DNA binding site [39].
  • One hundred twenty-eight compounds previously identified in a HIF-1-targeted cell-based high-throughput screen of the National Cancer Institute 140,000 small-molecule library were tested in a 96-well plate ELISA for inhibition of HIF-1 DNA-binding activity [40].
  • These results provide a compelling rationale for testing topotecan in clinical trials to target HIF-1 in cancer patients [41].


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  2. Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. Bos, R., Zhong, H., Hanrahan, C.F., Mommers, E.C., Semenza, G.L., Pinedo, H.M., Abeloff, M.D., Simons, J.W., van Diest, P.J., van der Wall, E. J. Natl. Cancer Inst. (2001) [Pubmed]
  3. Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. Karhausen, J., Furuta, G.T., Tomaszewski, J.E., Johnson, R.S., Colgan, S.P., Haase, V.H. J. Clin. Invest. (2004) [Pubmed]
  4. Hypoxia-inducible erythropoietin gene expression in human neuroblastoma cells. Stolze, I., Berchner-Pfannschmidt, U., Freitag, P., Wotzlaw, C., Rössler, J., Frede, S., Acker, H., Fandrey, J. Blood (2002) [Pubmed]
  5. Tumor hypoxia and cancer progression. Zhou, J., Schmid, T., Schnitzer, S., Brüne, B. Cancer Lett. (2006) [Pubmed]
  6. Physiological activation of hypoxia inducible factor-1 in human skeletal muscle. Ameln, H., Gustafsson, T., Sundberg, C.J., Okamoto, K., Jansson, E., Poellinger, L., Makino, Y. FASEB J. (2005) [Pubmed]
  7. Early expression of angiogenesis factors in acute myocardial ischemia and infarction. Lee, S.H., Wolf, P.L., Escudero, R., Deutsch, R., Jamieson, S.W., Thistlethwaite, P.A. N. Engl. J. Med. (2000) [Pubmed]
  8. Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL. Hon, W.C., Wilson, M.I., Harlos, K., Claridge, T.D., Schofield, C.J., Pugh, C.W., Maxwell, P.H., Ratcliffe, P.J., Stuart, D.I., Jones, E.Y. Nature (2002) [Pubmed]
  9. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Maxwell, P.H., Wiesener, M.S., Chang, G.W., Clifford, S.C., Vaux, E.C., Cockman, M.E., Wykoff, C.C., Pugh, C.W., Maher, E.R., Ratcliffe, P.J. Nature (1999) [Pubmed]
  10. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Semenza, G.L. Annu. Rev. Cell Dev. Biol. (1999) [Pubmed]
  11. The regulation of glucose metabolism by HIF-1 mediates a neuroprotective response to amyloid beta peptide. Soucek, T., Cumming, R., Dargusch, R., Maher, P., Schubert, D. Neuron (2003) [Pubmed]
  12. Leukocyte adhesion during hypoxia is mediated by HIF-1-dependent induction of beta2 integrin gene expression. Kong, T., Eltzschig, H.K., Karhausen, J., Colgan, S.P., Shelley, C.S. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  13. Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction. Wang, G.L., Semenza, G.L. Blood (1993) [Pubmed]
  14. The regulation of hypoxic genes by calcium involves c-Jun/AP-1, which cooperates with hypoxia-inducible factor 1 in response to hypoxia. Salnikow, K., Kluz, T., Costa, M., Piquemal, D., Demidenko, Z.N., Xie, K., Blagosklonny, M.V. Mol. Cell. Biol. (2002) [Pubmed]
  15. Induction of plasminogen activator inhibitor I gene expression by intracellular calcium via hypoxia-inducible factor-1. Liu, Q., Möller, U., Flügel, D., Kietzmann, T. Blood (2004) [Pubmed]
  16. Identification and characterization of a novel human histone H3 lysine 36-specific methyltransferase. Sun, X.J., Wei, J., Wu, X.Y., Hu, M., Wang, L., Wang, H.H., Zhang, Q.H., Chen, S.J., Huang, Q.H., Chen, Z. J. Biol. Chem. (2005) [Pubmed]
  17. Targeting gene expression to hypoxic tumor cells. Dachs, G.U., Patterson, A.V., Firth, J.D., Ratcliffe, P.J., Townsend, K.M., Stratford, I.J., Harris, A.L. Nat. Med. (1997) [Pubmed]
  18. Huntingtin interacts with a family of WW domain proteins. Faber, P.W., Barnes, G.T., Srinidhi, J., Chen, J., Gusella, J.F., MacDonald, M.E. Hum. Mol. Genet. (1998) [Pubmed]
  19. Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFbeta(3). Caniggia, I., Mostachfi, H., Winter, J., Gassmann, M., Lye, S.J., Kuliszewski, M., Post, M. J. Clin. Invest. (2000) [Pubmed]
  20. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Wang, G.L., Semenza, G.L. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  21. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Wang, G.L., Jiang, B.H., Rue, E.A., Semenza, G.L. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  22. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Manalo, D.J., Rowan, A., Lavoie, T., Natarajan, L., Kelly, B.D., Ye, S.Q., Garcia, J.G., Semenza, G.L. Blood (2005) [Pubmed]
  23. YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1. Yeo, E.J., Chun, Y.S., Cho, Y.S., Kim, J., Lee, J.C., Kim, M.S., Park, J.W. J. Natl. Cancer Inst. (2003) [Pubmed]
  24. Two transactivation mechanisms cooperate for the bulk of HIF-1-responsive gene expression. Kasper, L.H., Boussouar, F., Boyd, K., Xu, W., Biesen, M., Rehg, J., Baudino, T.A., Cleveland, J.L., Brindle, P.K. EMBO J. (2005) [Pubmed]
  25. Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Huang, L.E., Gu, J., Schau, M., Bunn, H.F. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  26. Identification of the full-length huntingtin- interacting protein p231HBP/HYPB as a DNA-binding factor. Rega, S., Stiewe, T., Chang, D.I., Pollmeier, B., Esche, H., Bardenheuer, W., Marquitan, G., Pützer, B.M. Mol. Cell. Neurosci. (2001) [Pubmed]
  27. EGFR tyrosine kinase inhibitors decrease VEGF expression by both hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms. Pore, N., Jiang, Z., Gupta, A., Cerniglia, G., Kao, G.D., Maity, A. Cancer Res. (2006) [Pubmed]
  28. Roles of Brahma and Brahma/SWI2-related gene 1 in hypoxic induction of the erythropoietin gene. Wang, F., Zhang, R., Beischlag, T.V., Muchardt, C., Yaniv, M., Hankinson, O. J. Biol. Chem. (2004) [Pubmed]
  29. Extracellular acidosis elevates carbonic anhydrase IX in human glioblastoma cells via transcriptional modulation that does not depend on hypoxia. Ihnatko, R., Kubes, M., Takacova, M., Sedlakova, O., Sedlak, J., Pastorek, J., Kopacek, J., Pastorekova, S. Int. J. Oncol. (2006) [Pubmed]
  30. Structural basis for negative regulation of hypoxia-inducible factor-1alpha by CITED2. Freedman, S.J., Sun, Z.Y., Kung, A.L., France, D.S., Wagner, G., Eck, M.J. Nat. Struct. Biol. (2003) [Pubmed]
  31. Suppression of the dual-specificity phosphatase MKP-1 enhances HIF-1 trans-activation and increases expression of EPO. Liu, C., Shi, Y., Han, Z., Pan, Y., Liu, N., Han, S., Chen, Y., Lan, M., Qiao, T., Fan, D. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  32. Epstein-Barr virus latent membrane protein 1 induces synthesis of hypoxia-inducible factor 1 alpha. Wakisaka, N., Kondo, S., Yoshizaki, T., Murono, S., Furukawa, M., Pagano, J.S. Mol. Cell. Biol. (2004) [Pubmed]
  33. Direct transcriptional up-regulation of cyclooxygenase-2 by hypoxia-inducible factor (HIF)-1 promotes colorectal tumor cell survival and enhances HIF-1 transcriptional activity during hypoxia. Kaidi, A., Qualtrough, D., Williams, A.C., Paraskeva, C. Cancer Res. (2006) [Pubmed]
  34. Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. Jiang, B.H., Rue, E., Wang, G.L., Roe, R., Semenza, G.L. J. Biol. Chem. (1996) [Pubmed]
  35. Hypoxic regulation of angiopoietin-2 expression in endothelial cells. Pichiule, P., Chavez, J.C., LaManna, J.C. J. Biol. Chem. (2004) [Pubmed]
  36. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. Berra, E., Benizri, E., Ginouvès, A., Volmat, V., Roux, D., Pouysségur, J. EMBO J. (2003) [Pubmed]
  37. Proteasomal inhibition attenuates transcriptional activity of hypoxia-inducible factor 1 (HIF-1) via specific effect on the HIF-1alpha C-terminal activation domain. Kaluz, S., Kaluzová, M., Stanbridge, E.J. Mol. Cell. Biol. (2006) [Pubmed]
  38. Targeting tumor-associated carbonic anhydrase IX in cancer therapy. Thiry, A., Dogn??, J.M., Masereel, B., Supuran, C.T. Trends Pharmacol. Sci. (2006) [Pubmed]
  39. General applicability of chicken egg yolk antibodies: the performance of IgY immunoglobulins raised against the hypoxia-inducible factor 1alpha. Camenisch, G., Tini, M., Chilov, D., Kvietikova, I., Srinivas, V., Caro, J., Spielmann, P., Wenger, R.H., Gassmann, M. FASEB J. (1999) [Pubmed]
  40. Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Kong, D., Park, E.J., Stephen, A.G., Calvani, M., Cardellina, J.H., Monks, A., Fisher, R.J., Shoemaker, R.H., Melillo, G. Cancer Res. (2005) [Pubmed]
  41. Schedule-dependent inhibition of hypoxia-inducible factor-1alpha protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts. Rapisarda, A., Zalek, J., Hollingshead, M., Braunschweig, T., Uranchimeg, B., Bonomi, C.A., Borgel, S.D., Carter, J.P., Hewitt, S.M., Shoemaker, R.H., Melillo, G. Cancer Res. (2004) [Pubmed]
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