Antiestrogens coactivators

Smith CL, Nawaz Z, O Malley BW (1997) Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. Mol Endocrinol 11 657... 

Fig. 6.2. Proposed mechanisms of action of pure antiestrogens (fulvestrant). 1 Fulvestrant (ICI) binds to estrogen receptor (ER). 2 Fulvestrant binding to ER accelerates receptor degradation ( ER down-regulator ). 3 Rate of dimerization and nuclear localization of fulvestrant-ER complex is reduced. 4 Reduced binding of fulvestrant-ER to ERE. 5 No transcription of estrogen-responsive genes since AF-1 and AF-2 are inactive, no coactivators are recruited and the activity of RNA polymerase II is not activated (or inhibited) (Wakeling 2000)...

AF-2 core, in such a way that HI 2 covers the hydrophobic pocket in the LBD, thus precluding the binding of coactivators (Brzozowski et al, 1997 Shiau et al, 1998). Such exciting findings provide an explanation for the mechanism of action of antiestrogens, or at least raloxifene. 

Fig. 8. Schematic representation of the ligand-induced changes in the confirmation of ER that lead to activities ranging from pure estrogenic (A) to pure antiestrogenic (D) effects. In addition to the ligand-induced changes in the three-dimensional structure of ER, the multiple interactions with cell-specific coactivators and corepressors determine the final activity of each ER-ligand complex in each cell type.

The antiestrogenic and some of the estrogen-iike actions of SERMs can be expiained by the different conformations of the ER-a compiexes attracting novei coactivators or corepressors (CoR) (Fig. 46.5) to moduiate estrogen action at different sites, in this modei, the receptor wouid be the same at each site, yet the coactivators and corepressors wouid be distributed differentiy at different targets (130). 

Ruegg J, Swedenborg E, Wahlstrom D, Escande A, Balaguer P, Pettersson K, Pongratz I (2008) The transcription factor aryl hydrocarbon receptor nuclear translocator functions as an estrogen receptor beta-selective coactivator, and its recruitment to alternative pathways mediates antiestrogenic effects of dioxin. Mol Endocrinol 22 304—316... 

The opening of a flexible pocket, thanks to the steric effect of the basic chain of raloxifene stabilized by an acid-base association with aspartate 351 of helix 12, does not permit binding of the coactivators in breast tissue. This is the reason for the antagonist effect observed. A similar effect has been observed with tamoxifen, as well as with ERp [12,13]. It will be seen later that some of the effects observed with organometallic estrogens and antiestrogens are attributable to the same cause. 

Smith CL, Nawaz Z, O Malley BW (1997) Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. Mol Endocrinol 11 657-666 Xu L, Lavinsky RM, Dasen JS, Flynn SE, Mclnemey EM, Mullen TM, Heinzel T, Szeto D, Korzus E, Kurokawa R et al (1998) Signal-specific co-activator domain requirements for Pit-1 activation. Nature 395 301-306... 

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