ASC-2 as an Anti-atherosclerotic coactivator

다국어 초록 (Multilingual Abstract)

The nuclear receptor superfamily is a group of proteins that regulate, in a ligand-dependent manner, transcriptional initiation of target genes by binding to specific DNA sequences named hormone response elements. Genetic studies indicated that transcription coactivators without specific DNA-binding activity are essential for transcriptional activation, which led to the identification of many proteins interacting with the C-terminal ligand-dependent transactivation domain of nuclear receptors. These coactivators, including the p160 family, CBP/p300, p/CAF, TRAP/DRIP and many others, bridge transcription factors and the basal transcription apparatus and/or remodel the chromatin structures.
ASC-2, also named AIB3, TRBP, RAP250, NRC and PRIP, is a recently isolated transcriptional coactivator molecule, which is gene-amplified and overexpressed in human cancers and stimulates transactivation by nuclear receptors, AP-1, NFkB, SRF, and numerous other transcription factors. In particular, the single cell microinjection results with ASC-2 antibody demonstrated that the endogenous ASC-2 is required for transactivation by nuclear receptors and AP-1. More recently, ASC-2 was found to exist in a steady-state complex of 2 MDa, which also contains histone H3-lysine 4-specific methyltransferase enzymes. Interestingly, ASC-2 contains two nuclear receptor-interaction domains, both of which are dependent on the integrity of their core LXXLL sequences. The C-terminal LXXLL motif specifically interacts with the liver X receptor (LXR)α and LXRβ, whereas the N-terminal motif binds a broad range of nuclear receptors.
LXRα(NR1H3) and LXRβ(NR1H2) are known to be important regulators of cholesterol metabolism and transport. Activation of LXR in macrophages results in increased expression of genes encoding ATP-binding cassette(ABC) cholesterol transporters ABCA1 and ABCG1 and apolipoprotein E that are involved with cholesterol efflux from macrophages toward high density lipoproteins. Furthermore, recent studies have identified LXRs as inhibitors of atherosclerosis. In the liver, LXR is involved in transcriptional control of Cyp7A1, encoding a critical enzyme in the conversion of cholesterol into bile acids, as well as ABCG5/ABCG8, encoding ABC transporters implicated in biliary cholesterol excretion. LXR has also been reported to control genes that encode proteins involved in de novo lipogenesis. In particular, induced transcription has been reported for the gene encoding SREBP-1c, the transcription factor that regulates expression of various lipogenic genes, including those encoding acetyl-CoA carboxylase and fatty acid synthase. In addition, LXR is known to directly influence transcription of genes encoding fatty acid synthase, lipoprotein lipase, cholesterol ester transfer protein, and stearoyl-CoA desaturase-1.
Gene targeting approaches to elucidate the role of many coactivators in mice have often been hampered by early embryonic lethality or functional redundancy. In particular, deletion of the ASC-2 gene also resulted in early embryonic lethality. As an alternative approach, we have recently expressed a dominant negative fragment of ASC-2 encompassing the C-terminal LXR-specific LXXLL motif(i.e., DN2) in mice, which inhibits the recruitment of the endogenous ASC-2 to LXRs and potently represses transactivation by LXRs in cotransfections. These DN2-TG mice exhibited phenotypes that are highly homologous to those previously observed with LXRα(-/-) mice and decreased transcription of many LXR target genes. To study the role of ASC-2 in atherosclerosis development, bone marrow transplantations were used to express DN2 only in macrophage in the context of murine models of atherosclerosis. Our results demonstrate that ASC-2 is an endogenous inhibitor of atherosclerosis. Together with the previously reported DN1-TG mice results, these results strongly suggest that ASC-2 is a physiologically pivotal transcriptional coactivator protein of LXRs and other nuclear receptors in vivo.