All-trans and 9-cis retinoic acid induction of CRABPII transcription is mediated by RAR-RXR heterodimers bound to DR1 and DR2 repeated motifs.
Two cooperating retinoic acid response elements (RAREs) in the cellular retinoic acid-binding protein II (CRABPII) gene mediate differential transcriptional transactivation by retinoic acid receptors (RARs) and retinoid X receptors (RXRs) in P19 embryonal carcinoma cells. RARE1 and RARE2 are direct repeats (DR) of two motifs separated by 2 bp (DR2) and 1 bp (DR1), respectively, and bind RAR-RXR heterodimers more efficiently than homodimers. Using all-trans and 9-cis RA, which differentially activate RARs and RXRs, and RAR and RXR dominant-negative mutants, RAR-RXR heterodimers bound to RARE1 and RARE2 are shown to be responsible for CRABPII promoter transactivation, arguing against a unique DR spacing specifying recognition by RARs. Within heterodimers, RAR and RXR independently and differentially transactivate, depending on the specific RARE. Consistent with these results, 9-cis RA increases CRABPII mRNA levels more efficiently than all-trans RA. In contrast, all-trans and 9-cis RA have identical effects on induction of RAR beta 2 transcripts.
Durand
B
B
Laboratoire de Génétique Moléculaire des Eucaryotes, Centre National de la Recherche Scientifique, Faculté de Médecine, Strasbourg, France.
Saunders
M
M
Leroy
P
P
Leid
M
M
Chambon
P
P
D001483:Base Sequence; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*
D002352:Carrier Proteins; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D011956:Receptors, Cell Surface; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin