In this article we summarize the birth of the field of nuclear receptors, the discovery of untransformed and transformed isoforms of ligand-binding macromolecules, the discovery of the three-domain structure of the receptors, and the properties of the Hsp90-based heterocomplex responsible for the overall structure of the oligomeric receptor and many aspects of the biological effects. The discovery and properties of the subfamily of receptors called orphan receptors is also outlined. Novel molecular aspects of the mechanism of action of nuclear receptors and challenges to resolve in the near future are discussed.

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The ability to permit gene expression is managed by a set of relatively well known regulatory mechanisms. Nonetheless, this property can also be acquired during a life span as a consequence of environmental stimuli. Interestingly, some acquired information can be passed to the next generation of individuals without modifying gene information, but instead by the manner in which cells read and process such information. Molecular chaperones are classically related to the proper preservation of protein folding and anti-aggregation properties, but one of them, heat-shock protein 90 (Hsp90), is a refined sensor of protein function facilitating the biological activity of properly folded client proteins that already have a preserved tertiary structure. Interestingly, Hsp90 can also function as a critical switch able to regulate biological responses due to its association with key client proteins such as histone deacetylases or DNA methylases. Thus, a growing amount of evidence has connected the action of Hsp90 to post-translational modifications of soluble nuclear factors, DNA, and histones, which epigenetically affect gene expression upon the onset of an unfriendly environment. This response is commanded by the activation of the transcription factor heat-shock factor 1 (HSF1). Even though numerous stresses of diverse nature are known to trigger the stress response by activation of HSF1, it is still unknown whether there are different types of molecular sensors for each type of stimulus. In the present review, we will discuss various aspects of the regulatory action of HSF1 and Hsp90 on transcriptional regulation, and how this regulation may affect genetic assimilation mechanisms and the health of individuals.