Fusion protein of retinoic acid receptor alpha with promyelocytic leukemia protein or promyelocytic leukemia zinc finger protein recruits N-CoR-TBLR1 corepressor complex to repress transcription in vivo.
Fusion proteins of retinoic acid receptor alpha (RARalpha) with promyelocytic leukemia protein (PML-RARalpha) or with promyelocytic leukemia zinc finger protein (PLZF-RARalpha) are associated with and likely responsible for the development of acute promyelocytic leukemia. These oncoproteins retain the ability to bind DNA and retinoic acid through the RARalpha moiety. This enables them to repress RARalpha target genes in the absence of retinoic acid, but the underlying mechanisms remain to be investigated. Here we use the frog oocyte system to study transcriptional regulation by PML-RARalpha and PLZF-RARalpha in the context of chromatin. We first show that the endogenous corepressor N-CoR forms a complex with TBLR1 (transducin beta-like protein 1-related protein) and that both N-CoR and TBLR1 can interact with unliganded PML-RARalpha and PLZF-RARalpha in vivo. Using chromatin immunoprecipitation, we demonstrate that both oncoproteins recruit TBLR1, as well as N-CoR, to its target promoter, leading to histone deacetylation and transcriptional repression. Furthermore, expression of a dominant negative N-CoR that contains the TBLR1-interacting domain blocks transcription repression by unliganded PML-RARalpha and PLZF-RARalpha. Thus, our studies provide in vivo evidence for targeted recruitment of N-CoR-TBLR1 complexes by PML-RARalpha and PLZF-RARalpha in transcriptional repression in the context of chromatin.
Tomita
Akihiro
A
Unit on Molecular Morphogenesis, Lab. of Gene Regulation and Development, NICHD, National Institutes of Health, Bethesda, Maryland 20892-5431, USA.
Buchholz
Daniel R
DR
Obata
Keiko
K
Shi
Yun-Bo
YB
D000595:Amino Acid Sequence; D000818:Animals; D002843:Chromatin / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D008024:Ligands; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D000071156:Promyelocytic Leukemia Protein; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D013489:Suppression, Genetic; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D025521:Tumor Suppressor Proteins; D014981:Xenopus; D029867:Xenopus Proteins / Q000737:chemistry / Q000378:metabolism*
D002843:Chromatin; D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D008024:Ligands; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D000075722:Promyelocytic Leukemia Zinc Finger Protein; C000607071:RARA protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D000072482:Retinoic Acid Receptor alpha; C473691:TBL1XR1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D029867:Xenopus Proteins; C470195:nuclear receptor corepressor, Xenopus; C070576:PML protein, human; C092037:ZBTB16 protein, human