Interaction between the amino- and carboxyl-terminal regions of the rat androgen receptor modulates transcriptional activity and is influenced by nuclear receptor coactivators

Identical N-terminal deletions in the wild-type rat androgen receptor (rAR) and a constitutively active rAR (AR Delta 641-902) devoid of the ligand-binding domain (LED) resulted in dissimilar consequences in transcriptional activation: deletion of residues 149-295 abolished wild-type AR activity, but did not influence that of AR Delta 641-902. The activity of the N-terminal transactivation domain is thus controlled by the hormone-occupied LED, suggesting that the N- and C-terminal regions of rAR communicate. Consistent with this idea, a strong androgen-dependent interaction between the N-terminal region and LED was demonstrated in a mammalian two-hybrid system using GAL4 and VP16 fusion proteins. This interaction can be direct or indirect. Several nuclear receptor coactivators (CEP, F-SRC-1, SRC-1, and RIP140) that interact with other steroid receptors were tested as potential mediators of the Nand C-terminal interaction of rAR using the mammalian two-hybrid system. CBP or F-SRC-1 not only enhanced AR-mediated transactivation, but also facilitated the androgen-dependent interaction between the N- and C-terminal domains, implying that part of the coactivator-dependent transcriptional activation occurs via this mechanism. In contrast, SRC-1, a coactivator for the progesterone receptor, inhibited both AR-mediated transactivation and interaction between the Pd and C termini. Recruitment of coregulators may involve AR domains other than the LED, as F-SRC-1 and CBP enhanced, but SRC-1 repressed, the transcriptional activity of AR Delta 641-902. Collectively, interplay between the N-terminal region and LED of rAR results in the formation of a transactivation complex that includes coregulators and that is mandatory for optimal activation of androgen-induced promoters.