Differential regulation of ligand-dependent and ligand-independent functions of the mouse retinoid X receptor beta by alternative splicing.
RXR is involved in two distinct signal transduction pathways. RXR activates transcription ligand-dependently on RXRE and behaves as a positive heterodimer partner with permissive receptors; while it behaves as a ligand-independent silent partner with nonpermissive receptors. We studied the functions of a unique isoform of mouse RXRbeta2 (mRXRbeta2E) which has an in-frame four-amino-acid insertion in the ligand binding domain. mRXRbeta2E did not bind 9-cis RA with high affinity and did not activate transcription on RXRE. However, mRXRbeta2E formed heterodimers with TR, VDR, RAR, and LXR, and enhanced transcriptional activity of the nonpermissive VDR to the same extent as mRXRbeta2. With the permissive LXR, mRXRbeta2E did not show 9-cis RA-dependent transactivation and inhibited mRXRbeta2 activity. Thus, although mRXRbeta2E can perform ligand-independent functions of RXR, it cannot mediate the ligand-dependent functions of RXR, indicating that alternative splicing plays an important role in the differential regulation of these two important functions of RXR.
Fujita
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A
The Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Mitsuhashi
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T
D000077556:Alitretinoin; D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D008024:Ligands; D051379:Mice; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D047488:Retinoid X Receptors; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D018411:Spodoptera / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics; D014212:Tretinoin / Q000378:metabolism
D004268:DNA-Binding Proteins; D008024:Ligands; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D000077556:Alitretinoin; D014212:Tretinoin