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Molecular endocrinology (Baltimore, Md.)
Sep, 2008;22 (9): 2061-75.

SUMO-mediated inhibition of glucocorticoid receptor synergistic activity depends on stable assembly at the promoter but not on DAXX.

Sam R Holmstrom, Sergey Chupreta, Alex Yick-Lun So, Jorge A Iñiguez-Lluhí
Author Information
  1. Sam R Holmstrom: Department of Pharmacology, University of Michigan Medical School. Ann Arbor, Michigan 48109-0632, USA.
PMID: 18562626 DOI: 10.1210/me.2007-0581

Abstract

Multiple transcription factors, including members of the nuclear receptor family, harbor one or more copies of a short regulatory motif that limits synergistic transactivation in a context-dependent manner. These synergy control (SC) motifs exert their effects by serving as sites for posttranslational modification by small ubiquitin-like modifier (SUMO) proteins. By analyzing the requirements for both synergy control and SUMOylation in the glucocorticoid receptor (GR), we find that an intact ligand-binding domain and an engaged DNA- binding domain dimerization interface are necessary for effective synergy control. However, these features, which promote stable assembly of GR-DNA complexes, are required downstream of SUMOylation because their disruption or deletion does not interfere with SUMO modification. Remarkably, in the absence of these features, sensitivity to the effects of SUMOylation can be restored simply by stabilization of DNA interactions through a heterologous DNA binding domain. The data indicate that stable interaction with DNA is an important prerequisite for SUMO-dependent transcriptional inhibition. Analysis of genomic regions occupied by GR indicates that the effects of SC motif SUMOylation are most evident at multiple, near-ideal GR binding sites and that SUMOylation selectively affects the induction of linked endogenous genes. Although the SUMO-binding protein DAXX has been proposed to mediate the inhibitory effects of GR SUMOylation, we find that inhibition by DAXX is independent of GR SUMOylation. Furthermore, neither expression nor knockdown of DAXX influences SUMO effects on GR. We therefore propose that stable binding of GR to multiple sites on DNA allows for the SUMO-dependent recruitment of inhibitory factors distinct from DAXX.

References

  1. Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15758-63 [PMID: 14663148]
  2. Mol Cell Biol. 2001 Apr;21(7):2467-74 [PMID: 11259595]
  3. Genes Dev. 2006 Apr 15;20(8):966-76 [PMID: 16598039]
  4. Biochemistry. 1992 Sep 22;31(37):9040-4 [PMID: 1390690]
  5. Genes Dev. 1989 Oct;3(10):1590-601 [PMID: 2515114]
  6. J Biol Chem. 2006 Aug 4;281(31):21848-21856 [PMID: 16760465]
  7. Annu Rev Biochem. 2004;73:355-82 [PMID: 15189146]
  8. Mol Endocrinol. 1996 Nov;10(11):1399-406 [PMID: 8923466]
  9. J Biol Chem. 2002 Aug 16;277(33):30283-8 [PMID: 12060666]
  10. EMBO J. 1989 Aug;8(8):2257-63 [PMID: 2792086]
  11. Mol Cell Biol. 2005 Mar;25(5):1879-90 [PMID: 15713642]
  12. Cell. 2002 Jan 11;108(1):109-20 [PMID: 11792325]
  13. Biochem Biophys Res Commun. 2000 Dec 9;279(1):6-10 [PMID: 11112409]
  14. J Biol Chem. 2001 Apr 20;276(16):12654-9 [PMID: 11124955]
  15. J Biol Chem. 2002 Mar 15;277(11):8999-9009 [PMID: 11779867]
  16. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8283-7 [PMID: 1924286]
  17. J Biol Chem. 2004 Jun 25;279(26):27233-8 [PMID: 15123604]
  18. Pigment Cell Res. 2005 Aug;18(4):265-77 [PMID: 16029420]
  19. Genes Dev. 2001 Dec 1;15(23):3088-103 [PMID: 11731474]
  20. Mol Endocrinol. 2008 Mar;22(3):570-84 [PMID: 18063693]
  21. J Biol Chem. 2001 Jun 15;276(24):21664-9 [PMID: 11259410]
  22. Horm Metab Res. 2004 Jun;36(6):387-91 [PMID: 15241729]
  23. J Biol Chem. 2004 Sep 10;279(37):38730-5 [PMID: 15192092]
  24. Proc Natl Acad Sci U S A. 2004 Oct 5;101(40):14373-8 [PMID: 15388847]
  25. Mol Cell. 2002 Oct;10(4):831-42 [PMID: 12419227]
  26. J Biol Chem. 2000 Apr 21;275(16):12298-305 [PMID: 10766869]
  27. Mol Endocrinol. 2003 Dec;17(12):2583-92 [PMID: 12933902]
  28. Biochem J. 2002 Nov 1;367(Pt 3):907-11 [PMID: 12144530]
  29. Mol Cell. 2004 Feb 27;13(4):611-7 [PMID: 14992729]
  30. Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14145-50 [PMID: 11121022]
  31. J Biol Chem. 2000 Mar 3;275(9):6252-8 [PMID: 10692421]
  32. PLoS Genet. 2007 Jun;3(6):e94 [PMID: 17559307]
  33. Mol Endocrinol. 1996 Aug;10(8):958-66 [PMID: 8843412]
  34. Mol Cell. 2006 Nov 3;24(3):341-54 [PMID: 17081986]
  35. Mol Endocrinol. 2007 Dec;21(12):2890-906 [PMID: 17717077]
  36. Mol Cell. 2003 Apr;11(4):1043-54 [PMID: 12718889]
  37. J Biol Chem. 2005 Mar 18;280(11):9937-45 [PMID: 15637059]
  38. Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13225-30 [PMID: 14578449]
  39. J Biol Chem. 2005 Jan 7;280(1):146-55 [PMID: 15507434]
  40. Biochemistry. 2007 Aug 28;46(34):9795-804 [PMID: 17676930]
  41. Gene. 2000 May 2;248(1-2):1-14 [PMID: 10806345]
  42. J Biol Chem. 2002 Sep 13;277(37):33950-6 [PMID: 12114521]
  43. J Clin Endocrinol Metab. 2003 Jan;88(1):277-84 [PMID: 12519866]
  44. J Biol Chem. 2003 May 9;278(19):16809-19 [PMID: 12615929]
  45. Cell. 2002 Feb 8;108(3):345-56 [PMID: 11853669]
  46. Endocrinology. 2006 Jan;147(1):590-8 [PMID: 16210365]
  47. Mol Endocrinol. 2004 Oct;18(10):2451-62 [PMID: 15192080]
  48. J Biol Chem. 1993 May 5;268(13):9629-35 [PMID: 8486650]
  49. DNA Cell Biol. 1990 Jun;9(5):355-68 [PMID: 2372377]
  50. Nature. 1995 Jun 1;375(6530):377-82 [PMID: 7760929]
  51. J Biol Chem. 2005 Mar 18;280(11):10164-73 [PMID: 15637079]
  52. Nature. 1991 Aug 8;352(6335):497-505 [PMID: 1865905]
  53. Mol Cell Biol. 2005 May;25(10):4272-82 [PMID: 15870296]
  54. J Biol Chem. 2007 Dec 14;282(50):36155-66 [PMID: 17940278]
  55. Mol Cell Biol. 1990 Oct;10(10):5529-31 [PMID: 2398899]
  56. J Biol Chem. 2006 Jun 9;281(23):16117-27 [PMID: 16524884]
  57. J Biol Chem. 2004 Oct 8;279(41):42410-21 [PMID: 15280358]
  58. Mol Cell Biol. 2000 Aug;20(16):6040-50 [PMID: 10913186]
  59. J Biol Chem. 1997 Feb 21;272(8):4843-9 [PMID: 9030541]
  60. Circ Res. 2003 Jun 13;92(11):1201-8 [PMID: 12750312]
  61. Cell. 2002 Jul 12;110(1):93-105 [PMID: 12151000]
  62. J Biol Chem. 2005 Feb 11;280(6):4102-10 [PMID: 15590687]
  63. Mol Cell. 2003 Jul;12(1):63-74 [PMID: 12887893]
  64. Cell Stress Chaperones. 2004 Autumn;9(3):243-52 [PMID: 15544162]
  65. Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5308-13 [PMID: 16567619]
  66. Mol Endocrinol. 2004 Jun;18(6):1438-49 [PMID: 15031320]
  67. Biochem Biophys Res Commun. 2005 Nov 18;337(2):517-20 [PMID: 16198310]
  68. Nature. 2005 Jun 2;435(7042):687-92 [PMID: 15931224]
  69. Nature. 1987 Jan 22-28;325(6102):365-8 [PMID: 3808033]
  70. Mol Endocrinol. 2003 Dec;17(12):2529-42 [PMID: 14500761]
  71. Br J Haematol. 2007 Nov;139(4):559-67 [PMID: 17979943]
  72. EMBO J. 2002 Oct 1;21(19):5206-15 [PMID: 12356736]
  73. Endocrinology. 1984 Jan;114(1):274-9 [PMID: 6690272]
  74. Gene. 2002 Aug 21;296(1-2):65-73 [PMID: 12383504]
  75. Biochem Biophys Res Commun. 2002 Jul 12;295(2):495-500 [PMID: 12150977]
  76. J Biol Chem. 2003 Mar 14;278(11):9134-41 [PMID: 12511558]
  77. Mol Cell. 2008 Mar 28;29(6):742-54 [PMID: 18374648]
  78. Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):45-50 [PMID: 16371476]
  79. EMBO J. 1988 Nov;7(11):3389-95 [PMID: 2463158]
  80. Nucleic Acids Res. 2006 Apr 13;34(7):e53 [PMID: 16614444]
  81. Cell. 1998 May 15;93(4):531-41 [PMID: 9604929]
  82. Genes Cells. 2005 Aug;10(8):835-50 [PMID: 16098147]

Grants

  1. R01 CA020535/NCI NIH HHS
  2. P60 DK20572/NIDDK NIH HHS
  3. R56 DK061656/NIDDK NIH HHS
  4. CA020535/NCI NIH HHS
  5. P60 DK020572/NIDDK NIH HHS
  6. R37 CA020535/NCI NIH HHS
  7. DK61656/NIDDK NIH HHS
  8. R01 DK061656/NIDDK NIH HHS

MeSH Term

Adaptor Proteins, Signal Transducing
Amino Acid Motifs
Animals
Base Sequence
COS Cells
Cell Line
Chlorocebus aethiops
Co-Repressor Proteins
DNA
Dimerization
Humans
Molecular Chaperones
Nuclear Proteins
Promoter Regions, Genetic
Protein Structure, Quaternary
RNA, Messenger
RNA, Small Interfering
Rats
Receptors, Glucocorticoid
Small Ubiquitin-Related Modifier Proteins
Transcriptional Activation

Chemicals

Adaptor Proteins, Signal Transducing
Co-Repressor Proteins
DAXX protein, human
Molecular Chaperones
Nuclear Proteins
RNA, Messenger
RNA, Small Interfering
Receptors, Glucocorticoid
Small Ubiquitin-Related Modifier Proteins
DNA
Journal Article Research Support, N.I.H., Extramural

Word Cloud

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