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This version published online on January 14, 2005
Molecular Endocrinology, doi:10.1210/me.2004-0331
A more recent version of this article appeared on May 1, 2005
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Submitted on August 24, 2004
Accepted on January 4, 2005

The elongation factor ELL is a selective coregulator for steroid receptor functions

Laurent PASCUAL-LE TALLEC, Federico SIMONE, Say VIENGCHAREUN, Geri MEDURI, Michael J THIRMAN, and Marc LOMBÈS*

INSERM, U478, IFR Claude Bernard, Faculté de Médecine Xavier Bichat, 75870 Paris cedex 18, FRANCE; University of Chicago, Section of Hematology/Oncology, Chicago, IL 60637-1470, USA; Laboratoire d'Hormonologie et de Génétique Moléculaire, Hôpital du Kremlin Bicêtre, 94270, Bicêtre, France

* To whom correspondence should be addressed. E-mail: marc.lombes{at}kb.u-psud.fr.

The dynamic and coordinated recruitment of coregulators by steroid receptors is critical for specific gene transcriptional activation. To identify new cofactors of the human mineralocorticoid receptor (hMR), its highly specific N-terminal domain was used as bait in a yeast two-hybrid approach. We isolated ELL (Eleven-nineteen Lysine rich Leukemia), a RNA polymerase II elongation factor which, when fused to MLL (Mixed Lineage Leukemia) contributes to the pathogenesis of acute leukemia. Specific interaction between hMR and ELL was confirmed by GST pull-down and coimmunoprecipitation experiments. Transient transfections demonstrated that ELL increased receptor transcriptional potency and hormonal efficacy, indicating that ELL behaves as a bona fide MR coactivator. Of major interest, ELL differentially modulates steroid receptor responses, with striking opposite effects on hMR and glucocorticoid receptor-mediated transactivation, without affecting that of androgen and progesterone receptors. Furthermore, the MLL-ELL fusion protein as well as several ELL truncated mutants lost their ability to potentiate MR transcriptional activities, suggesting that both the elongation domain and the ELL Associated Factor 1 (EAF1) interaction domains are required for ELL to fulfill its selector activity on steroid receptors. This study is the first direct demonstration of a functional interaction between a nuclear receptor and an elongation factor. These results provide further evidence that the selectivity of the mineralo vs. glucocorticoid signaling pathways also occurs at the transcriptional complex level and may have major pathophysiological implications most notably in leukemogenesis and corticosteroid-induced apoptosis. These findings allow us to propose the concept of "transcriptional selector" for ELL on steroid receptor transcriptional functions.

NURSA Molecule Pages Link:

Nuclear Receptors:   GR  |  MR  |  PR  |  AR
Coregulators:   ELL
Ligands:   Dexamethasone  |  Hydrocortisone  |  Dihydrotestosterone  |  Aldosterone  |  Progesterone



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