Mechanisms and significance of nuclear receptor auto- and cross-regulation

Abstract

The number of functional hormone receptors expressed by a cell in large part determines its responsiveness to the hormonal signal. The regulation of hormone receptor gene expression is therefore a central component of hormone action. Vertebrate steroid and thyroid hormones act by binding to nuclear receptors (NR) that function as ligand-activated transcription factors. Nuclear receptor genes are regulated by diverse and interacting intracellular signaling pathways. Nuclear receptor ligands can regulate the expression of the gene for the NR that mediates the hormone's action (autoregulation), thus influencing how a cell responds to the hormone. Autoregulation can be either positive or negative, the hormone increasing or decreasing, respectively, the expression of its own NR. Positive autoregulation (autoinduction) is often observed during postembryonic development, and during the ovarian cycle, where it enhances cellular sensitivity to the hormonal signal to drive the developmental process. By contrast, negative autoregulation (autorepression) may become important in the juvenile and adult for homeostatic negative feedback responses. In addition to autoregulation, a NR can influence the expression other types of NRs (cross-regulation), thus modifying how a cell responds to a different hormone. Cross-regulation by NRs is an important means to temporally coordinate cell responses to a subsequent (different) hormonal signal, or to allow for crosstalk between hormone signaling pathways.

Figure 1

Molecular mechanisms for regulation of nuclear receptor (NR) expression. The level of functional NRs in a cell can be regulated at transcriptional or posttranscriptional levels, or some combination of the two. A. Direct transcriptional regulation involves the hormone (filled oval)-NR complex (NRA; shown as a homodimer, but type II NRs also function as heterodimers) directly binding to a hormone response element located within the nra gene that activates or represses its expression (for cross-regulation the NRA binds to and regulates a different NR gene). Some NRs may influence target genes through hormone response elements that are far upstream or downstream of the regulated locus. Also, some NRs regulate target genes through protein-protein interactions rather than by direct DNA binding. B. Indirect transcriptional regulation involves the hormone-NRA complex inducing the expression of a gene that codes for a transcription factor (TF) that then positively or negatively regulates nra gene transcription (for cross-regulation the NRA regulates a TF that binds to and regulate a different NR gene). C. Cooperative transcriptional regulation involves both direct and indirect transcriptional mechanisms shown in parts A and B. D. The NRA may regulate the expression of a gene that increases or decreases stability of the nra mRNA (for cross-regulation, the mRNA for a different NR gene). E. Hormone binding to the NRA can stabilize it, thus increasing its half-life (t ½). F. The NRA may induce expression of a ubiquitin ligase that ubiquitinates (Ub) NRs in the cell (either the NRA or a different NR) and targets it to the proteasome for degradation. NR protein stability and bioactivity may also be influenced through posttranslational modifications such as (e.g., phosphorylation).

Figure 2

Forms of nuclear receptor (NR) cross-regulation. Hormone-bound NRs can regulate the expression of other types of NRs, and NR cross-regulation can take several forms. A. Unidirectional cross regulation involves a NR (NRA) regulating the expression of a different NR (NRB) while NRB does not affect the expression of NRA. B. In reciprocal positive cross-regulation, the hormone-bound NR (NRA) positively regulates the expression of another type of NR (NRB) and at the same time, hormone-bound NRB upregulates the expression of NRA. C. Reciprocal negative cross-regulation occurs when a hormone-bound NR (NRA) downregulates expression of another NR (NRB), and hormone-bound NRB negatively regulates expression of NRA. D. In another form of cross-regulation, a hormone-bound NR (NRA) positive regulates the expression of another NR (NRB), while NRB downregulates expression of NRA.

Figure 3

Role of the thyroid hormone (TH)-induced immediate early transcription factor Krüppel-like factor 9 (KLF9) in TH receptor (TR) autoinduction. Ligand-bound TR-retinoid X receptor (RXR) heterodimers bind to and induce expression of klf9 and trb genes. The upregulation of KLF9 by TH precedes TRβ. KLF9 associates with the promoter region of TRβ and enhances TRβ autoinduction (Bagamadbad et al., 2008). Aside from being a TH direct target gene, klf9 is also a direct glucocorticoid receptor (GR) target gene that is induced by stress (Bonett et al., 2009; P. Bagamasbad, T. Ziera, S.A. Borden and R.J. Denver, unpublished data). Thyroid hormone and glucocorticoids synergistically activate KLF9 expression, thereby further enhancing TRβ autoinduction.