title: 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.
authors.affiliation: Center for Ligand and Transcription, Department of Biology, Chonnam National University, Kwangju 500-757, Korea.
authors.forename: S K
authors.initials: SK
authors.lastname: Lee
authors.forename: S Y
authors.initials: SY
authors.lastname: Jung
authors.forename: Y S
authors.initials: YS
authors.lastname: Kim
authors.forename: S Y
authors.initials: SY
authors.lastname: Na
authors.forename: Y C
authors.initials: YC
authors.lastname: Lee
authors.forename: J W
authors.initials: JW
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D050882:CREB-Binding Protein; D002460:Cell Line; D004926:Escherichia coli; D015870:Gene Expression; D005982:Glutathione Transferase / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D056918:Nuclear Receptor Coactivators; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D016133:Polymerase Chain Reaction; D017433:Protein Structure, Secondary; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000737:chemistry / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D001616:beta-Galactosidase / Q000235:genetics; D000098825:Oxysterol Binding Proteins
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C486559:NCOA6 protein, human; C405683:Ncoa6 protein, mouse; D009687:Nuclear Proteins; D056918:Nuclear Receptor Coactivators; D010446:Peptide Fragments; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000098825:Oxysterol Binding Proteins; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C494364:Crebbp protein, mouse; D005982:Glutathione Transferase; D001616:beta-Galactosidase