Two distinct nuclear receptor-interaction domains and CREB-binding protein-dependent transactivation function of activating signal cointegrator-2.
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.
Mesh Terms:
Amino Acid Sequence, Animals, Binding Sites, CREB-Binding Protein, Cell Line, Escherichia coli, Gene Expression, Glutathione Transferase, Hela Cells, Humans, Intracellular Signaling Peptides and Proteins, Mice, Nuclear Proteins, Nuclear Receptor Coactivators, Peptide Fragments, Plasmids, Polymerase Chain Reaction, Protein Structure, Secondary, Receptors, Cytoplasmic and Nuclear, Receptors, Steroid, Receptors, Thyroid Hormone, Recombinant Fusion Proteins, Saccharomyces cerevisiae, Structure-Activity Relationship, Trans-Activators, Transcription Factors, Transcriptional Activation, Transfection, beta-Galactosidase
Amino Acid Sequence, Animals, Binding Sites, CREB-Binding Protein, Cell Line, Escherichia coli, Gene Expression, Glutathione Transferase, Hela Cells, Humans, Intracellular Signaling Peptides and Proteins, Mice, Nuclear Proteins, Nuclear Receptor Coactivators, Peptide Fragments, Plasmids, Polymerase Chain Reaction, Protein Structure, Secondary, Receptors, Cytoplasmic and Nuclear, Receptors, Steroid, Receptors, Thyroid Hormone, Recombinant Fusion Proteins, Saccharomyces cerevisiae, Structure-Activity Relationship, Trans-Activators, Transcription Factors, Transcriptional Activation, Transfection, beta-Galactosidase
Mol. Endocrinol.
Date: Feb. 01, 2001
PubMed ID: 11158331
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