Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

SUMOylation of Tr2 orphan receptor involves Pml and fine-tunes Oct4 expression in stem cells

Nature Structural & Molecular Biology volume 14, pages 68–75 (2007)Cite this article

Abstract

The Tr2 orphan nuclear receptor can be SUMOylated, resulting in the replacement of coregulators recruited to the regulatory region of its endogenous target gene, Oct4. UnSUMOylated Tr2 activates Oct4, enhancing embryonal carcinoma-cell proliferation, and is localized to the promyelocytic leukemia (Pml) nuclear bodies. When its abundance is elevated, Tr2 is SUMOylated at Lys238 and seems to be released from the nuclear bodies to act as a repressor. SUMOylation of Tr2 induces an exchange of its coregulators: corepressor Rip140 replaces coactivator Pcaf, which switches Tr2 from an activator to a repressor. This involves dynamic partitioning of Tr2 into Pml-containing and Pml-free pools. These results support a model where SUMOylation-dependent partitioning and differential coregulator recruitment contribute to the maintenance of a homeostatic supply of activating, as opposed to repressive, Tr2, thus fine-tuning Oct4 expression and regulating stem-cell proliferation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Tr2 regulates Oct4 expression through DR1.
Figure 2: Tr2 SUMOylation by Ubc9 and Pias1.
Figure 3: Lys238 is essential for Tr2 SUMOylation.
Figure 4: Tr2 may partition in Pml nuclear bodies for SUMOylation.
Figure 5: SUMOylation of Tr2 switches its biological activity from activation to repression.
Figure 6: Tr2 SUMOylation in relationship to Oct4 expression and cell proliferation.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Wei, L.-N. & Hsu, Y.-C. Identification of a new gene expressed specifically in early mouse embryos. Dev. Growth Differ. 36, 187 (1994).

    Article  CAS  Google Scholar 

  2. Lee, C.-H., Copeland, N.G., Gilbert, D.J., Jenkins, N.A. & Wei, L.-N. Genomic structure, promoter identification and chromosomal mapping of a mouse nuclear orphan receptor expressed in embryos and adult testes. Genomics 30, 46–52 (1995).

    Article  CAS  Google Scholar 

  3. Lee, C.-H., Chang, L. & Wei, L.-N. Distinct expression patterns and biological activities of two isoforms of the mouse orphan receptor TR2. J. Endocrinol. 152, 245–255 (1997).

    Article  CAS  Google Scholar 

  4. Lee, C.-H. & Wei, L.-N. Characterization of an inverted repeat with a zero spacer (IR0)-type retinoic acid response element from the mouse nuclear orphan receptor TR2–11 gene. Biochemistry 38, 8820–8825 (1999).

    Article  CAS  Google Scholar 

  5. Chinpaisal, C., Lee, C.-H. & Wei, L.-N. Mechanisms of the mouse orphan nuclear receptor TR2–11 mediated gene suppression. J. Biol. Chem. 273, 18077–18085 (1998).

    Article  CAS  Google Scholar 

  6. Shyr, C.R., Collins, L.L., Mu, X.M., Platt, K.A. & Chang, C. Spermatogenesis and testis development are normal in mice lacking testicular orphan nuclear receptor 2. Mol. Cell. Biol. 22, 4661–4666 (2002).

    Article  CAS  Google Scholar 

  7. Lee, C.-H., Chinpaisal, C. & Wei, L.-N. Cloning and characterization of mouse RIP140, a corepressor for nuclear orphan receptor TR2. Mol. Cell. Biol. 18, 6745–6755 (1998).

    Article  CAS  Google Scholar 

  8. Lin, T.M., Young, W.J. & Chang, C. Multiple functions of the TR2–11 orphan receptor in modulating activation of two key cis-acting elements involved in the retinoic acid signal transduction system. J. Biol. Chem. 270, 30121–30128 (1995).

    Article  CAS  Google Scholar 

  9. Wei, L.-N., Hu, X. & Chinpaisal, C. Constitutive activation of retinoic acid receptor β2 promoter by orphan nuclear receptor TR2. J. Biol. Chem. 275, 11907–11914 (2000).

    Article  CAS  Google Scholar 

  10. Khan, S.A., Park, S.W., Huq, M.D.M. & Wei, L.-N. Protein kinase C-mediated phosphorylation of orphan nuclear receptor TR2: effects on receptor stability and activity. Proteomics 5, 3885–3894 (2005).

    Article  CAS  Google Scholar 

  11. Khan, S.A., Park, S.W., Huq, M.D.M. & Wei, L.-N. Ligand-independent orphan receptor TR2 activation by phosphorylation at the DNA binding domain. Proteomics 6, 123–130 (2006).

    Article  CAS  Google Scholar 

  12. Okazawa, H. et al. The Oct3 gene, a gene for an embryonic transcription factor, is controlled by a retinoic acid repressible enhancer. EMBO J. 10, 2997–3005 (1991).

    Article  CAS  Google Scholar 

  13. Pikarsky, E., Sharia, H., Ben-Shushan, E. & Bergman, Y. Retinoic acid represses Oct-3/4 gene expression through several retinoic acid-responsive elements located in the promoter-enhancer region. Mol. Cell. Biol. 14, 1026–1038 (1994).

    Article  CAS  Google Scholar 

  14. Nichols, J. et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95, 379–391 (1998).

    Article  CAS  Google Scholar 

  15. Niwa, H., Miyazaki, J.-I. & Smith, A.G. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of WS cells. Nat. Genet. 24, 372–376 (2000).

    Article  CAS  Google Scholar 

  16. Chambers, I. & Smith, A. Self-renewal of teratocarcinoma and embryonic stem cells. Oncogene 23, 7150–7160 (2004).

    Article  CAS  Google Scholar 

  17. Ovitt, C.E. & Scholer, H.R. The molecular biology of Oct4 in the early mouse embryo. Mol. Hum. Reprod. 4, 1021–1031 (1998).

    Article  CAS  Google Scholar 

  18. Marin, M., Karis, A., Visser, P., Grosveld, F. & Philipsen, S. Transcription factor Sp1 is essential for early embryonic development but dispensable for cell growth and differentiation. Cell 89, 619–628 (1997).

    Article  CAS  Google Scholar 

  19. Barnea, E. & Bergman, Y. Synergy of SF1 and RAR in activation of Oct-3/4 promoter. J. Biol. Chem. 275, 6608–6619 (2000).

    Article  CAS  Google Scholar 

  20. Gu, P. et al. Orphan nuclear receptor GCNF is required for the repression of pluripoptency genes during retinoic acid-induced embryonic stem cell differentiation. Mol. Cell. Biol. 25, 8507–8519 (2005a).

    Article  CAS  Google Scholar 

  21. Gu, P. et al. Orphan nuclear receptor LRH-1 is required to maintain Oct4 expression at the epiblast stage of embryonic development. Mol. Cell. Biol. 25, 3492–3505 (2005b).

    Article  CAS  Google Scholar 

  22. Schoorlemmer, J. et al. Characterization of a negative retinoic acid response element in the murine Oct4 promoter. Mol. Cell. Biol. 14, 1122–1136 (1994).

    Article  CAS  Google Scholar 

  23. Anckar, J. et al. Inhibition of DNA binding by differential sumoylation of heat shock factors. Mol. Cell. Biol. 26, 955–964 (2006).

    Article  CAS  Google Scholar 

  24. Lee, M.B. et al. The DEAD-box protein DP103 (Ddx20 or Gemin-3) represses orphan nuclear receptor activity via SUMO modification. Mol. Cell. Biol. 25, 1879–1890 (2005).

    Article  CAS  Google Scholar 

  25. Pascual, G. et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-γ. Nature 437, 759–763 (2005).

    Article  CAS  Google Scholar 

  26. Yang, S.H. & Sharrocks, A.D. SUMO promotes HDAC-mediated transcriptional repression. Mol. Cell 13, 611–617 (2004).

    Article  CAS  Google Scholar 

  27. Ross, S., Best, B., Zon, L. & Gill, G. SUMO-1 modification represses Sp3 transcriptional activation and modulates its subnuclear localization. Mol. Cell 10, 831–842 (2002).

    Article  CAS  Google Scholar 

  28. Quimby, B.B., Yong-Gonzalez, V., Anan, T., Strunnikov, A.V. & Dasso, M. The promyelocytic leukemia protein stimulates SUMO conjugation in yeast. Oncogene 25, 2999–3005 (2006).

    Article  CAS  Google Scholar 

  29. Lee, C.-H., Chang, L. & Wei, L.-N. Molecular cloning and characterization of a mouse nuclear orphan receptor expressed in embryos and testes. Mol. Reprod. Dev. 44, 305–314 (1996).

    Article  CAS  Google Scholar 

  30. Yang, M., Hsu, C.T., Ting, C.Y., Liu, L.F. & Hwang, J. Assembly of a polymeric chain of SUMO1 on human topoisomerase I in vitro. J. Biol. Chem. 281, 8264–8274 (2006).

    Article  CAS  Google Scholar 

  31. Rodriguez, M.S., Dargemont, C. & Hay, R.T. SUMO-1 conjugation in vivo requires both a consensus modification motif and nuclear targeting. J. Biol. Chem. 276, 12654–12659 (2001).

    Article  CAS  Google Scholar 

  32. Rochette-Egly, C. Dynamic combinatorial networks in nuclear receptor-mediated transcription. J. Biol. Chem. 280, 32565–32568 (2005).

    Article  CAS  Google Scholar 

  33. Wu, R.C., Smith, C.L. & O'Malley, B.W. Transcriptional regulation by steroid receptor coactivator phosphorylation. Endocr. Rev. 26, 393–399 (2005).

    Article  CAS  Google Scholar 

  34. Lonard, D.M. & O'Malley, B.W. Expanding functional diversity of the coactivators. Trends Biochem. Sci. 30, 126–132 (2005).

    Article  CAS  Google Scholar 

  35. Gill, G. Something about SUMO inhibits transcription. Curr. Opin. Genet. Dev. 15, 536–541 (2005).

    Article  CAS  Google Scholar 

  36. Johnson, E.S. Protein modification by SUMO. Annu. Rev. Biochem. 73, 355–382 (2004).

    Article  CAS  Google Scholar 

  37. Ulrich, H.D. SUMO modification: wrestling with protein conformation. Curr. Biol. 15, R257–R259 (2005).

    Article  CAS  Google Scholar 

  38. Hay, R.T. SUMO: a history of modification. Mol. Cell 18, 1–12 (2005).

    Article  CAS  Google Scholar 

  39. Yang, H.M. et al. Characterization of putative cis-regulatory elements that control the transcriptional activity of the human Oct4 promoter. J. Cell. Biochem. 96, 821–830 (2005).

    Article  CAS  Google Scholar 

  40. Spengler, M.L. & Brattain, M.G. Sumoylation inhibits cleavage of Sp1 N-terminal negative regulatory domain and inhibits Sp1-dependent transcription. J. Biol. Chem. 281, 5567–5574 (2006).

    Article  CAS  Google Scholar 

  41. Sentis, S., Romancer, M.L., Bianchin, C., Rostan, M.C. & Corbo, L. Sumoylation of the estrogen receptor alpha hinge region regulates its transcriptional activity. Mol. Endocrinol. 19, 2671–2684 (2005).

    Article  CAS  Google Scholar 

  42. Chalkiadaki, A. & Talianidis, I. SUMO-dependent compartmentalization in promyelocytic leukemia protein nuclear bodies prevents the access of LRH-1 to chromatin. Mol. Cell. Biol. 25, 5095–5105 (2005).

    Article  CAS  Google Scholar 

  43. Gross, M., Yang, R., Top, I., Gasper, C. & Shuai, K. PIASy-mediated repression of the androgen receptor is independent of sumoylation. Oncogene 23, 3059–3066 (2004).

    Article  CAS  Google Scholar 

  44. Chauchereau, A., Amazit, L., Quesne, M., Guiochon-Mantel, A. & Milgrom, E. Sumoylation of the progesterone receptor and of the steroid receptor coactivator SRC-1. J. Biol. Chem. 278, 12335–12343 (2003).

    Article  CAS  Google Scholar 

  45. Tian, S., Poukka, H., Palvimo, J.J. & Jänne, O.A. Small ubiquitin-related modifier-1 (SUMO-1) modification of the glucocorticoid receptor. Biochem. J. 367, 907–911 (2002).

    Article  CAS  Google Scholar 

  46. Dellaire, G. & Bazett-Jones, D.P. PML nuclear bodies: dynamic sensors of DNA damage and cellular stress. Bioessays 26, 963–977 (2005).

    Article  Google Scholar 

  47. Bossis, G. & Melchior, F. Regulation of SUMOylation by reversible oxidation of SUMO conjugating enzymes. Mol. Cell 21, 349–357 (2006).

    Article  CAS  Google Scholar 

  48. Park, S.W. et al. Thyroid hormone-induced juxtaposition of regulatory elements/factors and chromatin remodeling of Crabp1 dependent on MED1/TRAP220. Mol. Cell 19, 643–653 (2005).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by US National Institutes of Health grants DK54733, DK60521, K02 DA13926 and DA11190 to L.-N.W. We also thank C.H. Lee and C. Chainpaisal for yeast screening and N.P. Tsai, F.C. Walosin and S.D. Persaud for technical support.

Author information

Author notes

  1. Xinli Hu

    Present address: Department of Medicine, University of Minnesota Medical School,

Authors and Affiliations

  1. Department of Pharmacology, University of Minnesota Medical School, Minneapolis, 55455, Minnesota, USA

    Sung Wook Park, Xinli Hu, Pawan Gupta, Ya-Ping Lin, Sung Gil Ha & Li-Na Wei

Authors
  1. Sung Wook Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xinli Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pawan Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ya-Ping Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sung Gil Ha
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Li-Na Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.W.P. initiated the study of differential regulation of Oct4 by Tr2, designed and performed experiments and analyzed data. X.H. initiated and performed experiments on SUMOylation of Tr2 and constructed plasmids. P.G. conducted immunoprecipitations, mammalian two-hybrid assays and RNA interference experiments. Y.-P.L. conducted RT-PCR and ChIP assays. S.G.H. conducted immunofluorescence microscopy. L.-N.W. supervised the entire project and provided all the financial support.

Corresponding author

Correspondence to Li-Na Wei.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Park, S., Hu, X., Gupta, P. et al. SUMOylation of Tr2 orphan receptor involves Pml and fine-tunes Oct4 expression in stem cells. Nat Struct Mol Biol 14, 68–75 (2007). https://doi.org/10.1038/nsmb1185

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb1185

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing