Fusion protein of retinoic acid receptor α with promyelocytic leukemia protein or promyelocytic leukemia zinc finger protein recruits N-CoR-TBLR1 corepressor complex to repress transcription in vivo

Akihiro Tomita, Daniel R. Buchholz, Keiko Obata, Yun Bo Shi

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36 Citations (Scopus)

Abstract

Fusion proteins of retinoic acid receptor a (RARα) with promyelocytic leukemia protein (PML-RARα) or with promyelocytic leukemia zinc finger protein (PLZF-RARα) 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 RARα moiety. This enables them to repress RARα 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-RARα and PLZF-RARα 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-RARα and PLZF-RARα 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-RARα and PLZF-RARα. Thus, our studies provide in vivo evidence for targeted recruitment of N-CoR-TBLR1 complexes by PML-RARα and PLZF-RARα in transcriptional repression in the context of chromatin.

Original languageEnglish
Pages (from-to)30788-30795
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number33
DOIs
Publication statusPublished - 15-08-2003
Externally publishedYes

Fingerprint

Co-Repressor Proteins
Retinoic Acid Receptors
Zinc Fingers
Transcription
Zinc
Leukemia
Fusion reactions
Proteins
Chromatin
Oncogene Proteins
Tretinoin
Promyelocytic Leukemia Protein
Transducin
Acute Promyelocytic Leukemia
Chromatin Immunoprecipitation
Anura
Histones
Oocytes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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title = "Fusion protein of retinoic acid receptor α with promyelocytic leukemia protein or promyelocytic leukemia zinc finger protein recruits N-CoR-TBLR1 corepressor complex to repress transcription in vivo",
abstract = "Fusion proteins of retinoic acid receptor a (RARα) with promyelocytic leukemia protein (PML-RARα) or with promyelocytic leukemia zinc finger protein (PLZF-RARα) 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 RARα moiety. This enables them to repress RARα 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-RARα and PLZF-RARα 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-RARα and PLZF-RARα 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-RARα and PLZF-RARα. Thus, our studies provide in vivo evidence for targeted recruitment of N-CoR-TBLR1 complexes by PML-RARα and PLZF-RARα in transcriptional repression in the context of chromatin.",
author = "Akihiro Tomita and Buchholz, {Daniel R.} and Keiko Obata and Shi, {Yun Bo}",
year = "2003",
month = "8",
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T1 - Fusion protein of retinoic acid receptor α with promyelocytic leukemia protein or promyelocytic leukemia zinc finger protein recruits N-CoR-TBLR1 corepressor complex to repress transcription in vivo

AU - Tomita, Akihiro

AU - Buchholz, Daniel R.

AU - Obata, Keiko

AU - Shi, Yun Bo

PY - 2003/8/15

Y1 - 2003/8/15

N2 - Fusion proteins of retinoic acid receptor a (RARα) with promyelocytic leukemia protein (PML-RARα) or with promyelocytic leukemia zinc finger protein (PLZF-RARα) 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 RARα moiety. This enables them to repress RARα 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-RARα and PLZF-RARα 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-RARα and PLZF-RARα 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-RARα and PLZF-RARα. Thus, our studies provide in vivo evidence for targeted recruitment of N-CoR-TBLR1 complexes by PML-RARα and PLZF-RARα in transcriptional repression in the context of chromatin.

AB - Fusion proteins of retinoic acid receptor a (RARα) with promyelocytic leukemia protein (PML-RARα) or with promyelocytic leukemia zinc finger protein (PLZF-RARα) 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 RARα moiety. This enables them to repress RARα 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-RARα and PLZF-RARα 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-RARα and PLZF-RARα 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-RARα and PLZF-RARα. Thus, our studies provide in vivo evidence for targeted recruitment of N-CoR-TBLR1 complexes by PML-RARα and PLZF-RARα in transcriptional repression in the context of chromatin.

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