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Ubiquitination-dependent cofactor exchange on LIM homeodomain transcription factors

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Abstract

The interactions of distinct cofactor complexes with transcription factors are decisive determinants for the regulation of gene expression. Depending on the bound cofactor, transcription factors can have either repressing or transactivating activities1. To allow a switch between these different states, regulated cofactor exchange has been proposed2,3; however, little is known about the molecular mechanisms that are involved in this process. LIM homeodomain (LIM-HD) transcription factors associate with RLIM (RING finger LIM domain-binding protein) and with CLIM (cofactor of LIM-HD proteins; also known as NLI, Ldb and Chip) cofactors. The co-repressor RLIM inhibits the function of LIM-HD transcription factors, whereas interaction with CLIM proteins is important for the exertion of the biological activity conferred by LIM-HD transcription-factors4,5. Here we identify RLIM as a ubiquitin protein ligase that is able to target CLIM cofactors for degradation through the 26S proteasome pathway. Furthermore, we demonstrate a ubiquitination-dependent association of RLIM with LIM-HD proteins in the presence of CLIM cofactors. Our data provide a mechanistic basis for cofactor exchange on DNA-bound transcription factors, and probably represent a general mechanism of transcriptional regulation.

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Figure 1: RLIM is a ubiquitin protein ligase that is able to ubiquitinate LMO proteins and CLIM cofactors in vitro.
Figure 2: RLIM targets CLIM2 and LMO2 proteins for degradation.
Figure 3: In vivo degradation of CLIM cofactors is mediated by RLIM.
Figure 4: Functional protein interactions of RLIM.
Figure 5: Cofactor exchange on LIM-HD proteins.

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References

  1. Mannervik, M., Nibu, Y., Zhang, H. & Levine, M. Transcriptional coregulators in development. Science 284, 606–609 (1999).

    Article  CAS  Google Scholar 

  2. Glass, C. K. & Rosenfeld, M. G. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 14, 121–141 (2000).

    CAS  PubMed  Google Scholar 

  3. Shang, Y., Hu, X., DiRenzo, J., Lazar, M. A. & Brown, M. Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell 103, 843–852 (2000).

    Article  CAS  Google Scholar 

  4. Bach, I. The LIM domain: regulation by association. Mech. Dev. 91, 5–17 (2000).

    Article  CAS  Google Scholar 

  5. Hobert, O. & Westphal, H. Functions of LIM homeobox genes. Trends Genet. 16, 75–83 (2000).

    Article  CAS  Google Scholar 

  6. Agulnick, A. D. et al. Interactions of the LIM-domain-binding factor Ldb1 with LIM homeodomain proteins. Nature 384, 270–272 (1996).

    Article  ADS  CAS  Google Scholar 

  7. Morcillo, P., Rosen, C., Baylies, M. K. & Dorsett, D. Chip, a widely expressed chromosomal protein required for segmentation and activity of a remote wing margin enhancer in Drosophila. Genes Dev. 11, 2729–2740 (1997).

    Article  CAS  Google Scholar 

  8. Bach, I. et al. RLIM inhibits functional activity of LIM homeodomain transcription factors via recruitment of the histone deacetylase complex. Nature Genet. 22, 394–399 (1999).

    Article  CAS  Google Scholar 

  9. Milán, M. & Cohen, S. M. Regulation of LIM homeodomain activity in vivo: a tetramer of dLDB and Apterous confers activity and capacity for regulation by dLMO. Mol. Cell 4, 267–273 (1999).

    Article  Google Scholar 

  10. van Meyel, D. J. et al. Chip and Apterous physically interact to form a functional complex during Drosophila development. Mol. Cell 4, 259–265 (1999).

    Article  CAS  Google Scholar 

  11. van Meyel, D. J. et al. Chip is an essential cofactor for Apterous in the regulation of axon guidance in Drosophila. Development 127, 1823–1831 (2000).

    CAS  PubMed  Google Scholar 

  12. Milán, M., Diaz-Benjumea, F. J. & Cohen, S. M. Beadex encodes an LMO protein that regulates Apterous LIM-homeodomain activity in Drosophila wing development: a model for LMO oncogene function. Genes Dev. 12, 2912–2920 (1998).

    Article  Google Scholar 

  13. Hershko, A. & Ciechanover, A. The ubiquitin system. Annu. Rev. Biochem. 67, 425–479 (1998).

    Article  CAS  Google Scholar 

  14. Tiedt, R., Bartholdy, B. A., Matthias, G., Newell, J. W. & Matthias, P. The RING finger protein Siah-1 regulates the level of the transcriptional coactivator OBF-1. EMBO J. 20, 4143–4152 (2001).

    Article  CAS  Google Scholar 

  15. Boehm, J., He, Y., Greiner, A., Staudt, L. & Wirth, T. Regulation of BOB.1/OBF-1 stability by SIAH. EMBO J. 20, 4153–4162 (2001).

    Article  CAS  Google Scholar 

  16. Joazeiro, C. A. P. & Weissman, A. M. RING finger proteins: mediators of ubiquitin ligase activity. Cell 79, 549–552 (2000).

    Article  Google Scholar 

  17. Pickart, C. M. Mechanisms underlying ubiquitination. Annu. Rev. Biochem. 70, 503–533 (2001).

    Article  CAS  Google Scholar 

  18. Lorick, K. L. et al. RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. Proc. Natl Acad. Sci. USA 96, 11364–11369 (1999).

    Article  ADS  CAS  Google Scholar 

  19. Windle, J. J., Weiner, R. I. & Mellon, P. L. Cell lines of the pituitary gonadotrope lineage derived by targeted oncogenesis in transgenic mice. Mol. Endocrinol. 4, 597–603 (1990).

    Article  CAS  Google Scholar 

  20. Ostendorff, H. P. et al. Functional characterization of the gene encoding RLIM, the corepressor of LIM homeodomain factors. Genomics 69, 120–130 (2000).

    Article  CAS  Google Scholar 

  21. Bach, I., Carrière, C., Ostendorff, H. P., Andersen, B. & Rosenfeld, M. G. A family of LIM domain interacting cofactors confer transcriptional synergism between LIM and Otx homeoproteins. Genes Dev. 11, 1370–1380 (1997).

    Article  CAS  Google Scholar 

  22. Jurata, L. W. & Gill, G. N. Functional analysis of the nuclear LIM domain interactor NLI. Mol. Cell Biol. 17, 5688–5698 (1997).

    Article  CAS  Google Scholar 

  23. Bach, I. et al. P-Lim, a LIM homeodomain factor, is expressed during pituitary organ and cell commitment and synergizes with Pit-1. Proc. Natl Acad. Sci. USA 92, 2720–2724 (1995).

    Article  ADS  CAS  Google Scholar 

  24. Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001).

    Article  ADS  CAS  Google Scholar 

  25. Bach, I. & Yaniv, M. More potent transcriptional activators or a transdominant inhibitor of the HNF1 homeoprotein family are generated by alternative RNA processing. EMBO J. 12, 4229–4242 (1993).

    Article  CAS  Google Scholar 

  26. Roberson, M. S., Schoderbek, W. E., Tremml, G. & Maurer, R. A. Activation of the glycoprotein hormone α-subunit promoter by a LIM-homeodomain transcription factor. Mol. Cell. Biol. 14, 2985–2993 (1994).

    Article  CAS  Google Scholar 

  27. Yu, V. C. et al. RXR β: a coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements. Cell 67, 1251–1266 (1991).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank P. Mellon for the gift of αT3 cells; A. Krones and Y. Alvarez for advice on ChIP assays and chick electroporations, respectively; T. Heinzel for Sin3 expression vectors; I. Hermans-Borgmeyer for comments on the manuscript; and Y. Bodingbauer for technical assistance. H.P.O. was a fellow of the Graduiertenkolleg 255 of the University of Hamburg, and I.B. is a Heisenberg scholar of the Deutsche Forschungsgemeinschaft (DFG). I.B. and M.S. are supported by grants from the DFG.

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Author notes

  1. Heather P. Ostendorff, Reto I. Peirano and Martin Scheffner: These authors contributed equally to this work

Authors and Affiliations

  1. Zentrum für Molekulare Neurobiologie Hamburg (ZMNH), Universität Hamburg, Martinistrasse 85, Hamburg, 20251, Germany

    Heather P. Ostendorff, Reto I. Peirano, Marvin A. Peters, Anne Schlüter, Michael Bossenz & Ingolf Bach

  2. Institut für Biochemie I, Medizinische Fakultät, Universität zu Köln, Joseph-Stelzmann-Strasse 52, Köln, 50931, Germany

    Martin Scheffner

Authors
  1. Heather P. Ostendorff
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  2. Reto I. Peirano
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  3. Marvin A. Peters
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  4. Anne Schlüter
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  5. Michael Bossenz
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  6. Martin Scheffner
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  7. Ingolf Bach
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Correspondence to Ingolf Bach.

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Ostendorff, H., Peirano, R., Peters, M. et al. Ubiquitination-dependent cofactor exchange on LIM homeodomain transcription factors. Nature 416, 99–103 (2002). https://doi.org/10.1038/416099a

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