Nuclear Receptors

Ligand-Independent Activation with Ets-1

Science's STKE  21 Nov 2000:
Vol. 2000, Issue 59, pp. tw2
DOI: 10.1126/stke.2000.59.tw2

Nuclear receptors of the steroid hormone receptor family are typically considered ligand-dependent transcriptional regulators. Tolón et al. found that if the Ets-1 transcription factor was co-expressed with the estrogen receptor (ER), the vitamin D receptor (VDR), or the peroxisome-proliferator-activated receptor (PPAR), then these receptors acted with the prolactin-specific transcription factor GHF-1 to cause ligand-independent activation of a reporter construct containing the prolactin promoter. Without Ets-1, a ligand (for example vitamin D for the VDR) was required in order to activate transcription. Ligand-independent activation by Ets-1 did not occur with the retinoid X receptor suggesting specificity to the Ets-1 interaction. This response was not limited to the prolactin promoter, but also occurred with the estrogen response element, the vitamin D response element, and the peroxisome-proliferator response element when Ets-1 and the cognate nuclear receptor were coexpressed with the reporter gene. Ets-1 directly interacted with the ER, VDR, and PPAR in coimmunoprecipitation and glutathione-S-transferase pull down experiments. The importance of this interaction in vivo was confirmed by the ability of the VDR and Ets-1 to coprecipitate from pituitary cells in both the presence and absence of vitamin D. Ets-1 belongs to a family of transcription factors regulated by mitogen-activated protein kinase (MAPK) cascade. Thus, this Ets-1-induced transcriptional activity represents one mechanism by which the MAPK signals can influence nuclear receptor activity even in the absence of the hormone.

Tolón, R.M., Castillo, A.I., Jiménez-Lara, A.M., and Aranda, A. (2000) Association with Ets-1 causes ligand- and AF2-independent activation of nuclear receptors. Mol. Cell. Biol. 20: 8793-8802. [Abstract] [Full Text]