N/C Interactions Are Dispensable for Normal In Vivo Functioning of the Androgen Receptor in Male Mice

Abstract

The androgen receptor (AR) plays a central role in the development and maintenance of the male phenotype. The binding of androgens to the receptor induces interactions between the carboxyterminal ligand-binding domain and the highly conserved 23FQNLF 27 motif in the amino-terminal domain. The role of these so-called N/C interactions in AR functioning is debated. In vitro assays show that mutating the AR in the 23FQNLF 27 motif (called AR NoC) attenuates the AR transactivation of reporter genes, has no effect on ligand binding, but does affect protein-protein interactions with several AR coregulators. To test the in vivo relevance of the N/C interaction, we analyzed the consequences of the genomic introduction of the AR NoC mutation in mice. Surprisingly, the AR NoC/Y mice show a normal male development, with unaffected male anogenital distance, normal accessory sex glands as well as male circulating androgen levels, body composition and fertility. The responsiveness of androgen target genes in kidney, prostate and testes was also unaffected. We thus conclude that the N/C interactions in the AR are not essential for the development of a male phenotype under normal physiological conditions.

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“…Surprisingly, this did not affect the AR function in a mutant mouse model. This finding challenges the in vivo role of this AR-specific dimerization mode but does not exclude its role in prostate cancer [ 50 ]. In contrast, disrupting the LBD dimerization of the AR by a point mutation in the mouse genome leads to androgen insensitivity in the absence of accessory sex glands despite much higher circulating testosterone levels.…”

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“…62,63 In vitro studies have also suggested critical interactions between the N-terminus and C-terminus in AR transactivation, although more contemporary in vivo work suggests that this property may be dispensible. 64 In recent years, various constitutively active AR-Vs have been characterized that lack the LBD and may command AR programs in a ligand-independent manner. [65][66][67][68] Importantly, the majority of current AR-directed agents either directly interact with or require a functioning LBD and thus do not act on AR-Vs.…”

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“…Ligand binding induces: 1) dissociation of AR from the HSP complex; 2) conformational changes including an N-to-C intramolecular interaction; and 3) activation of its nuclear localization signal followed by AR import into the nucleus (28,29). It is of note that the physiological function of AR N/C interactions are debated, as a recent paper showed reduced in vitro transactivation capacity by an AR mutant lacking N/C interactions in luciferase reporters, while no effect on male development was observed in mice bearing the same mutation (30). In the nucleus, AR interacts with its nuclear cofactors via its AF-1 and AF-2 (31,32) and both functions are suggested to have specificity for coregulator subsets, with the AF-1 being sufficient to drive AR target gene expression in the absence of AF-2.…”