The proliferating cell nuclear antigen regulates retinoic acid receptor transcriptional activity through direct protein-protein interaction.
Retinoic acid receptors (RARs) interact, in a ligand-dependent fashion, with many coregulators that participate in a wide spectrum of biological responses, ranging from embryonic development to cellular growth control. The transactivating function of these ligand-inducible transcription factors reside mainly, but not exclusively, in their ligand-binding domain (AF2), which recruits or dismiss coregulators in a ligand-dependent fashion. However, little is known about AF2-independent function(s) of RARs. We have isolated the proliferating cell nuclear antigen (PCNA) as a repressor of RAR transcriptional activity, able to interact with an AF2-crippled RAR. The N-terminus of PCNA interacts directly with the DNA-binding domain of RAR, and PCNA is recruited to a retinoid-regulated promoter in intact cells. This interaction affects the transcriptional response to retinoic acid in a promoter-specific manner, conferring an unanticipated role to PCNA in transcriptional regulation. Our findings also suggest a role for RAR as a factor coordinating DNA transcription and repair.
Martin
Perrine J
PJ
INSERM U459 and Ligue Nationale contre le Cancer, Faculté de Médecine de Lille 1 place de Verdun 59045 Lille cedex, France.
Lardeux
Virginie
V
Lefebvre
Philippe
P
D001665:Binding Sites; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D015533:Transcriptional Activation; D014212:Tretinoin / Q000494:pharmacology; D020798:Two-Hybrid System Techniques
D018809:Proliferating Cell Nuclear Antigen; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin