Increasing the Complexity of Coactivation in Nuclear Receptor Signaling

Although the sheer number of coactivators and the novel mechanisms by which they are recruited to receptors might appear mind-numbing, a recently characterized multisubunit complex that binds to vitamin D receptor (VDR) (Rachez et al. 1998xRachez, C., Suldan, Z., Ward, J., Chang, C.P., Burakov, D., Erdjument-Bromage, H., Tempst, P., and Freedman, L.P. Genes Dev. 1998; 12: 1787–1800Crossref | PubMedSee all ReferencesRachez et al. 1998), thyroid hormone receptor (TR) (Fondell et al. 1996xFondell, J.D., Ge, H., and Roeder, R.G. Proc. Natl. Acad. Sci. USA. 1996; 93: 8329–8333Crossref | PubMed | Scopus (402)See all ReferencesFondell et al. 1996), and, most likely, many other members of the nuclear receptor family, points to the ultimate generality of transactivation. This complex, called DRIP or TRAP, is recruited to the LBD AF2 core in response to ligand-binding through a single subunit (DRIP205/TRAP220) via one LXXLL motif in much the same manner as the p160 coactivators. DRIP205 anchors the other 14–16 proteins comprising the DRIP/TRAP complex to the receptor, thereby conferring hormone-dependent recruitment of what appears to be a preformed complex. DRIP/TRAP is required for ligand-dependent transcription activation in vitro, which notably has not yet been demonstrated for the p160 coactivators. Several DRIP/TRAP subunits are homologous to proteins described as components of Mediator (7xGu, W., Malik, S., Ito, M., Yuan, C.-X., Fondell, J.D., Zhang, X., Martinez, E., Qin, J., and Roeder, R.G. Mol. Cell. 1999; 3: 97–108Abstract | Full Text | Full Text PDF | PubMed | Scopus (224)See all References, 13xRachez, C., Suldan, Z., Ward, J., Chang, C.P., Burakov, D., Erdjument-Bromage, H., Tempst, P., and Freedman, L.P. Genes Dev. 1998; 12: 1787–1800Crossref | PubMedSee all References), a complex that together with SRB proteins associates with RNA polymerase II (Pol II) through its large subunit’s carboxy-terminal repeat domain (CTD). This suggests that DRIP/TRAP, perhaps through Mediator/SRB subunits, might function in part by targeting Pol II holoenzyme to promoters (Figure 2BFigure 2B). The generality of this complex stems from the unexpected observation that other activators unrelated to nuclear receptors, including Sp1, recruit the DRIP/TRAP complex or subcomplexes (called CRSP in Ryu et al. 1999xRyu, S., Zhou, S., Ladurner, A.G., and Tjian, R. Nature. 1999; 397: 446–450Crossref | PubMed | Scopus (282)See all ReferencesCRSP in Ryu et al. 1999), and that several of the DRIP/TRAP subunits are present in two similar, if not identical, SRB-interacting complexes, NAT and SMCC (18xSun, X., Zhang, Y., Cho, H., Rickert, P., Lees, E., Lane, W., and Reinberg, D. Mol. Cell. 1998; 2: 213–222Abstract | Full Text | Full Text PDF | PubMedSee all References, 7xGu, W., Malik, S., Ito, M., Yuan, C.-X., Fondell, J.D., Zhang, X., Martinez, E., Qin, J., and Roeder, R.G. Mol. Cell. 1999; 3: 97–108Abstract | Full Text | Full Text PDF | PubMed | Scopus (224)See all References). As studies on the DRIP/TRAP complex progress, it is expected that their role in transcriptional regulation will be further generalized; many classes of activators are likely to recruit coactivator complexes and subcomplexes containing the shared subunits of DRIP/TRAP and SRB/Mediator. This additionally suggests that nuclear receptors utilize a general mechanism for transactivation, but with inducibility imposed by ligand binding, which is required for the recruitment of the DRIP/TRAP complex.How the DRIP/TRAP complex interfaces with the p160/CBP/pCAF system, if at all, is perhaps one of the key questions regarding nuclear receptor coactivation presently. They may act independently or they may act in sequence, where the HAT coactivators remodel chromatin to then allow the DRIP/TRAP complex to recruit RNA polymerase II holoenzyme (Figure 2Figure 2). In this model, what influences the dissociation of the first complex and the binding of the second is unknown. What is certain is that as the number of coactivators and the complexes they form grow, the challenge of understanding their underlying molecular functions will continue to generate surprises and inspire insights into how gene transcription is so exquisitely regulated.