Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Mar;29(3):349-63.
doi: 10.1210/me.2014-1315. Epub 2015 Jan 27.

Minireview: Tipping the balance: ligand-independent activation of steroid receptors

Marcela A Bennesch  1 , Didier Picard
Affiliations
Review

Minireview: Tipping the balance: ligand-independent activation of steroid receptors

Marcela A Bennesch et al. Mol Endocrinol. 2015 Mar.

Abstract

Steroid receptors are prototypical ligand-dependent transcription factors and a textbook example for allosteric regulation. According to this canonical model, binding of cognate steroid is an absolute requirement for transcriptional activation. Remarkably, the simple one ligand-one receptor model could not be farther from the truth. Steroid receptors, notably the sex steroid receptors, can receive multiple inputs. Activation of steroid receptors by other signals, working through their own signaling pathways, in the absence of the cognate steroids, represents the most extreme form of signaling cross talk. Compared with cognate steroids, ligand-independent activation pathways produce similar but not identical outputs. Here we review the phenomena and discuss what is known about the underlying molecular mechanisms and the biological significance. We hypothesize that steroid receptors may have evolved to be trigger happy. In addition to their cognate steroids, many posttranslational modifications and interactors, modulated by other signals, may be able to tip the balance.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.. Conceptualization of ligand-independent activation of SRs as an extreme form of signaling cross talk.
From the situation represented schematically in panel A to that in panel C, there is a progressively stronger and stronger impact of signaling pathway 1 (in red) on signaling pathway 2 (in blue).
Figure 2.
Figure 2.. A multitude of signaling pathways can activate unliganded steroid receptors.
Many intra- and extracellular signals lead to the activation of kinases (or other transcription factors) that modulate SR and coregulator activities, thereby promoting the assembly of an alternative apo-SR transcription complex at target genes. For comparison, a more canonical SR transcription complex assembled in response to the cognate steroid is shown on the left (holo-SR transcription complex). For simplicity, the only additional signaling inputs that are indicated for this liganded complex are the ones from nongenomic steroid signaling through membrane-associated SRs (with broken arrows). The cognate steroid is symbolized as a yellow ball. Holo-SR and apo-SR are liganded and unliganded SRs, respectively. The complexity of phosphorylation sites is indicated by different colors.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Robinson-Rechavi M, Carpentier AS, Duffraisse M, Laudet V. How many nuclear hormone receptors are there in the human genome? Trends Genet. 2001;17:554–556. - PubMed
    1. Tsai MJ, O'Malley BW. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem. 1994;63:451–486. - PubMed
    1. Mangelsdorf DJ, Thummel C, Beato M, et al. . The nuclear receptor superfamily: the second decade. Cell. 1995;83:835–839. - PMC - PubMed
    1. Yamamoto KR. Steroid receptor regulated transcription of specific genes and gene networks. Annu Rev Genet. 1985;19:209–252. - PubMed
    1. Beato M, Truss M, Chávez S. Control of transcription by steroid hormones. Ann NY Acad Sci. 1996;784:93–123. - PubMed

Publication types

Grants and funding

This work was supported by the Canton de Genève, the Swiss National Science Foundation, and the Fondation Medic.