Nature 377, 451 - 454 (05 October 2002); doi:10.1038/377451a0

Polarity-specific activities of retinoic acid receptors determined by a co-repressor

Riki Kurokawa^*, Mats Söderström^*, Andreas Hörlein^†, Shlomit Halachmi^‡, Myles Brown^‡, Michael G. Rosenfeld^*§† & Christopher K. Glass^*§¶

^*Department of Medicine, Division of Endocrinology and Metabolism, Division of Cellular and Molecular Medicine, and ^†Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA
^‡Division of Neoplastic Disease Mechanisms, Dana Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA

RETINOIC acid receptors (RARs) and retinoid-X receptors (RXRs) activate or repress transcription by binding as heterodimers to DNA-response elements that generally consist of two direct repeat half-sites of consensus sequence AGGTCA (reviewed in ref. 1). On response elements consisting of direct repeats spaced by five base pairs (DR + 5 elements), RAR/RXR heterodimers activate transcription in response to RAR-specific ligands, such as all-trans-retinoic acid (RA)². In contrast, on elements consisting of direct repeats spaced by one base pair (DR + 1 elements), RAR/RXR heterodimers exhibit little or no response to activating ligands and repress RXR-dependent transcription³. Here we show that ligand-dependent transactivation by RAR on DR + 5 elements requires the dissociation of a new nuclear receptor co-repressor, N-CoR, and recruitment of the putative co-activators p140 and p160 (refs 4, 5). Surprisingly, on DR + 1 elements, N-CoR remains associated with RAR/RXR heterodimers even in the presence of RAR ligands, resulting in constitutive repression. These observations indicate that DNA-response elements can allosterically regulate RAR-co-repressor interactions to determine positive or negative regulation of gene expression.

References

1.	Glass, C. K. Endocr. Rev. 15, 1503−1519 (1994).
2.	Umesono, K., Murakami, K. K., Thompson, C. C. & Evans, R. M. Cell 65, 1255−1266 (1991). | Article | PubMed | ISI | ChemPort |
3.	Mangelsdorf, D. J. et al. Cell 66, 555−561 (1991). | Article | PubMed | ISI | ChemPort |
4.	Halachmi, S. et al. Science 264, 1455−1458 (1994). | PubMed | ISI | ChemPort |
5.	Cavailles, V., Dauvois, S., Danielian, P. S. & Parker, M. G. Proc. natn. Acad. Sci. U.S.A. 91, 10009−10013 (1994). | ISI | ChemPort |
6.	Kurokawa, R. et al. Nature 371, 528−531 (1994). | Article | PubMed | ISI | ChemPort |
7.	Kurokawa, R. et al. Genes Dev. 7, 1423−1435 (1993). | PubMed | ISI | ChemPort |
8.	Perlmann, T., Rangarajan, P. N., Umesono, K. & Evans, R. M. Genes Dev. 7, 1411−1422 (1993). | PubMed | ISI | ChemPort |
9.	Zechel, C. et al. EMBO J. 13, 1425−1433 (1994). | PubMed | ISI | ChemPort |
10.	Foreman, B. M., Umesono, K., Chen, J. & Evans, R. M. Cell 81, 541−550 (1995). | PubMed |
11.	Le Douarin, B. et al. EMBO J. 14, 2020−2033 (1995). | PubMed | ISI | ChemPort |
12.	Lee, J. W. et al. Nature 374, 91−94 (1995). | Article | PubMed | ISI | ChemPort |
13.	Danielian, P. S., White, R., Lees, J. A. & Parker, M. G. EMBO J. 11, 1025−1033 (1992). | PubMed | ISI | ChemPort |
14.	Durand, B. et al. EMBO J. 13, 5370−5382 (1994). | PubMed | ISI | ChemPort |
15.	Barettino, D., Vivanco Ruiz, M. M. & Stunnenberg, H. G. EMBO J. 13, 3039−3049 (1994). | PubMed | ISI | ChemPort |
16.	Tone, Y., Collingwood, T. N., Adams, M. & Chatterjee, V. K. J. biol Chem. 269, 31157−31161 (1994). | PubMed | ISI | ChemPort |
17.	Baniahmad, A. et al. Molec. cell. Biol. 15, 76−86 (1995). | PubMed | ChemPort |
18.	Casanova, J. et al. Molec. cell Biol. 14, 5756−5765 (1995).
19.	Hörlein, A. et al. Nature 377, 397−404 (1995). | Article | PubMed | ISI | ChemPort |
20.	Keidel, S., LeMotte, P. & Apfel, C. Molec. cell. Biol. 14, 287−298 (1994). | PubMed | ChemPort |
21.	Kaelin, W. G. Jr. et al. Cell 70, 351−364 (1992). | Article | PubMed | ISI | ChemPort |