Editors' ChoiceTranscription

Regulating the Repressor

Science's STKE  15 Aug 2000:
Vol. 2000, Issue 45, pp. tw8
DOI: 10.1126/stke.2000.45.tw8

The retinoic acid receptor and the thyroid hormone receptor are nuclear receptors that exert a repressive effect in the absence of ligand and a stimulatory effect in the presence of ligand. The repressive function is mediated through interactions with corepressor proteins, SMRT or N-CoR. Hong and Privalsky show that the interaction of SMRT with the thyroid hormone receptor is regulated by phosphorylation by mitogen-activated protein kinases (MAPK) activated by the epidermal growth factor receptor (EGFR). Using a reporter gene and cotransfection, the repression of transcription by the thyroid receptor was inhibited by coexpression of EGFR. SMRT and thyroid hormone interactions were measured by a mammalian two-hybrid system and were inhibited when the EGFR, MAPK-extracellular signal regulated kinase-1 (MEK-1), or MEK-1 kinase (MEKK-1) was also expressed. Coexpression of the EGFR, MEK-1, or MEKK-1 also resulted in the redistribution of SMRT from the nucleus to the cytoplasm. Futhermore, SMRT was a substrate for phosphorylation by MEK-1 and MEKK-1, and this phosphorylation disrupted its interaction with the thyroid receptor in vitro.

Hong, S.-H., and Privalsky, M.L. (2000) The SMRT corepressor is regulated by a MEK-1 kinase pathway: Inhibition of corepressor function is associated with SMRT phosphorylation and nuclear export. Mol. Cell. Biol. 20: 6612-6625. [Abstract] [Full Text]