A CBP Integrator Complex Mediates Transcriptional Activation and AP-1 Inhibition by Nuclear Receptors

Abstract

Nuclear receptors regulate gene expression by direct activation of target genes and inhibition of AP-1. Here we report that, unexpectedly, activation by nuclear receptors requires the actions of CREB-binding protein (CBP) and that inhibition of AP-1 activity is the apparent result of competition for limiting amounts of CBP/p300 in cells. Utilizing distinct domains, CBP directly interacts with the ligand-binding domain of multiple nuclear receptors and with the p160 nuclear receptor coactivators, which upon cloning have proven to be variants of the SRC-1 protein. Because CBP represents a common factor, required in addition to distinct coactivators for function of nuclear receptors, CREB, and AP-1, we suggest that CBP/p300 serves as an integrator of multiple signal transduction pathways within the nucleus.

Modulation of Fos-mediated AP-1 transcription by the promyelocytic leukemia protein

“…The mechanism of inhibition of PMLRARa's e ect on Fos activity by ATRA is currently unknown. It recently has been shown that ligand-activated steroid hormone receptors including RARa can interact directly with CBP through their ligand-binding/dimerization domain and inhibit the AP-1 activity possibly by competing for the limited amount of CBP in the cell (Chakravarti et al, 1996;Kamei et al, 1996). This is evident for the e ect of RARa on Fos activity in the presence of retinoic acid (compare lanes 5 and 10 in Figure 2).…”

“…CBP recently has been shown to speci®cally interact with Fos and Jun, functioning as a co-activator and hence stimulating AP-1 transcription Kamei et al, 1996). The C-terminal domain of Fos contains three Fos activation modules (see Figure 4a), which have been shown to cooperate with each other to activate transcription (Brown et al, 1995).…”

“…This is evident for the e ect of RARa on Fos activity in the presence of retinoic acid (compare lanes 5 and 10 in Figure 2). Therefore, it can be speculated that the possible binding of the mutant receptor to CBP through the ligand-binding/ dimerization of its RARa moiety in the presence of ATRA may have a ected its functional interaction with Fos (Kamei et al, 1996). Experiments analysing the functional and physical interaction of PML and PMLRARa with CBP are now underway.…”

“…These alterations are mediated by an array of factors such as ligand-activated steroid hormone receptors such as the glucocorticoid receptor and retinoic acid receptor (RAR), which function as regulators of AP-1 transcription (for reviews see Pfahl, 1993;Teurich and Angel, 1995). These ligand-activated steroid hormone receptors have recently been shown to interact speci®cally with the c-AMP response element binding protein (CREB) binding protein (CBP) (Chakravarti et al, 1996;Kamei et al, 1996). Because CBP interacts with c-Fos and c-Jun (major components of AP-1) and serves as their coactivator , it has been hypothesized that inhibition of AP-1 transcription by ligand-activated steroid hormone receptors is caused by competition for limited quantities of CBP in the cell (Kamei et al, 1996).…”

“…These ligand-activated steroid hormone receptors have recently been shown to interact speci®cally with the c-AMP response element binding protein (CREB) binding protein (CBP) (Chakravarti et al, 1996;Kamei et al, 1996). Because CBP interacts with c-Fos and c-Jun (major components of AP-1) and serves as their coactivator , it has been hypothesized that inhibition of AP-1 transcription by ligand-activated steroid hormone receptors is caused by competition for limited quantities of CBP in the cell (Kamei et al, 1996).…”