Two Distinct Nuclear Receptor-Interaction Domains and CREB-Binding Protein-Dependent Transactivation Function of Activating Signal Cointegrator-2

Abstract

ASC-2 is a recently isolated transcriptional cointegrator molecule, which is amplified in human cancers and stimulates transactivation by nuclear receptors, AP-1, nuclear factor kappaB (NFkappaB), serum response factor (SRF), and numerous other transcription factors. ASC-2 contained two nuclear receptor-interaction domains, both of which are dependent on the integrity of their core LXXLL sequences. Surprisingly, the C-terminal LXXLL motif specifically interacted with oxysterol receptor LXRss, whereas the N-terminal motif bound a broad range of nuclear receptors. These interactions appeared to be essential because a specific subregion of ASC-2 including the N- or C-terminal LXXLL motif acted as a potent dominant negative mutant with transactivation by appropriate nuclear receptors. In addition, the autonomous transactivation domain (AD) of ASC-2 was found to consist of three separable subregions; i.e. AD1, AD2, and AD3. In particular, AD2 and AD3 were binding sites for CREB binding protein (CBP), and CBP-neutralizing E1A repressed the autonomous transactivation function of ASC-2. Furthermore, the receptor transactivation was not enhanced by ASC-2 in the presence of E1A and significantly impaired by overexpressed AD2. From these results, we concluded that ASC-2 directly binds to nuclear receptors and recruits CBP to mediate the nuclear receptor transactivation in vivo.

Targeted inactivation of MLL3 histone H3–Lys-4 methyltransferase activity in the mouse reveals vital roles for MLL3 in adipogenesis

“…In addition, H3 and H4 acetylation were concomitantly induced (Fig. 4B and data not shown), as expected from the reported cross-talk between these 2 modifications (32,33) and between ASCOM and histone acetyltransferases CBP and p300 (34)(35)(36).…”

Protein kinase C α modulates liver X receptor α transactivation

“…PKCa modulates LXRa transactivation reporter genes (Rochette-Egly 2003). Indeed, co-activators specifically modulating the function of LXR have been identified such as activating signal cointegrator-2 (Lee et al 2001). More recent findings have demonstrated that glucose signaling alters the sub-cellular distribution of LXR, although there is no evidence that this is phosphorylation dependent (Helleboid-Chapman et al 2006).…”

The mechanism mediating the activation of acetyl-coenzyme A carboxylase-α gene transcription by the liver X receptor agonist T0-901317

“…One possibility is that SREBP-1 facilitates the recruitment of coactivators to T0-901317-bound LXR&RXR complexes. LXRa, LXRb, and SREBP-1 interact with several coactivator proteins, including CREB binding protein (CBP) and the TRAP/ARC/DRIP complex (42)(43)(44)(45)(46)(47). We postulate that the presence of SREBP-1 on ACCa promoter 2 provides additional coactivator interaction sites that stabilize the binding of CBP, TRAP/ ARC/DRIP, and other coactivators to T0-901317-bound LXR&RXR.…”