Steroid receptors bind as dimers to a degenerate set of response elements containing inverted repeats of a hexameric half-site separated by 3 bp of spacer (IR3). Naturally occurring selective androgen response elements have recently been identified that resemble direct repeats of the hexameric half-site (ADR3). The 3D crystal structure of the androgen receptor (AR) DNA-binding domain bound to a selective ADR3 reveals an unexpected head-tohead arrangement of the two protomers rather than the expected head-to-tail arrangement seen in nuclear receptors bound to response elements of similar geometry. Compared with the glucocorticoid receptor, the DNA-binding domain dimer interface of the AR has additional interactions that stabilize the AR dimer and increase the affinity for nonconsensus response elements. This increased interfacial stability compared with the other steroid receptors may account for the selective binding of AR to ADR3 response elements.T he androgen receptor (AR) is a ligand-activated transcription factor that plays a central role in male sexual development and in the etiology of prostate cancer (1, 2). It is a member of the steroid and nuclear hormone receptor superfamily, which also includes receptors for glucocorticoids (GR), mineralocorticoids (MR), progesterone (PR), estrogens (ER), and vitamin D (VDR) (3). Members of this family contain conserved, discrete, DNA-binding domains (DBDs) and ligand-binding domains. The amino-terminal domain and the hinge region connecting the central DBD to the C-terminal ligand-binding domain diverge among family members.The hormone receptor DBD consists of a highly conserved 66-residue core made up of two zinc-nucleated modules, shown schematically in Fig. 1 A (4, 5). With VDR as the only reported exception (6), the isolated DBD and associated C-terminal extension are necessary and sufficient to generate the same pattern of DNA response element selectivity, partner selection, and dimerization as the full-length receptor from which it is derived (6-11).Although ligand binding elicits distinct hormone-specific responses, all classical steroid receptors (AR, PR, MR, and GR) recognize identical DNA response elements, which consist of two hexameric half-sites (5Ј-AGAACA-3Ј) arranged as inverted repeats with 3 bp of separating DNA, producing the 2-fold IR3 sequence pattern (Fig. 1B) (12). A question that continues to engage the steroid receptor field is how these transcription factors achieve DNA target specificity despite this degeneracy. As seen in the structures of the GR and ER DBDs bound to IR3 elements (4, 13), the receptors bind as ''head-to-head'' homodimers whose symmetric displacement across the DNA pseudodyad reflects the underlying half-site arrangement. Differences in steroid metabolism, receptor expression, local chromatin structure, and the availability of cofactors all contribute to steroid-specific responses (14-17). However, recent work has now also identified selective androgen response elements (AREs). The AREs consist of two hexameric half-sites a...

Cells continually assess their energy and nutrient state to maintain growth and survival and engage necessary homeostatic mechanisms. Cell autonomous responses to the fed state require the surveillance of the availability of amino acids and other nutrients. The mammalian target of rapamycin complex 1 (mTORC1) integrates information on nutrient and amino acid availability to support protein synthesis and cell growth. We identify the G protein-coupled receptor (GPCR) T1R1/T1R3 as a direct sensor of the fed state and amino acid availability. Knocking down this receptor, which is found in most tissues, reduces the ability of amino acids to signal to mTORC1. Interfering with this receptor alters localization of mTORC1, downregulates expression of pathway inhibitors, upregulates key amino acid transporters, blocks translation initiation, and induces autophagy. These findings reveal a mechanism for communicating amino acid availability through a GPCR to mTORC1 in mammals.

MAP kinases transduce signals that are involved in a multitude of cellular pathways and functions in response to a variety of ligands and cell stimuli. Aberrant or inappropriate functions of MAPKs have now been identified in diseases ranging from cancer to inflammatory disease to obesity and diabetes. In many cell types, the MAPKs ERK1/2 are linked to cell proliferation. ERK1/2 are thought to play a role in some cancers, because mutations in Ras and B-Raf, which can activate the ERK1/2 cascade, are found in many human tumors. Abnormal ERK1/2 signaling has also been found in polycystic kidney disease, and serious developmental disorders such as cardio-facio-cutaneous syndrome arise from mutations in components of the ERK1/2 cascade. ERK1/2 are essential in well-differentiated cells and have been linked to long-term potentiation in neurons and in maintenance of epithelial polarity. Additionally, ERK1/2 are important for insulin gene transcription in pancreatic beta cells, which produce insulin in response to increases in circulating glucose to permit efficient glucose utilization and storage in the organism. Nutrients and hormones that induce or repress insulin secretion activate and/or inhibit ERK1/2 in a manner that reflects the secretory demand on beta cells. Disturbances in this and other regulatory pathways may result in the contribution of ERK1/2 to the etiology of certain human disorders.