title: Transcriptional repression by leukaemia-associated ETO family members can be independent of oligomerization and coexpressed hSIN3B and N-CoR.
abstract: The leukaemia-associated eight-twenty-one (ETO) family members ETO, MTG16 (Myeloid Translocation Gene on chromosome 16) and MTGR1 (Myeloid Transforming Gene-Related protein1) are putative transcriptional repressor proteins, which form complexes with coregulatory nuclear corepressors such as SIN3 (SWI-Independent) and N-CoR (Nuclear receptor Co Repressor). In acute myeloid leukaemia (AML), fusion proteins involving the transcription factor AML1 and corepressors ETO or MTG16 are recurrently found. We investigated transcriptional repression by the ETO family members ETO and MTG16 with attention to the conserved Nervy Homology Regions (NHRs) and the interacting corepressors human SIN3B (hSIN3B) and N-CoR. Transcriptional repression was examined in a cell line by a GAL4-thymidine kinase luciferase reporter to which the corepressors were tethered through a binding domain. ETO- and MTG16-mediated repression was found to be independent of deletion of the oligomerization NHR2, but deletion of NHR4 and in particular combined deletion of NHR2 and NHR4 lowered the capacity for repression. An interaction was observed between the corepressors hSIN3B and N-CoR and these two proteins cooperated for transcriptional repression independent of co-transfected ETO and MTG16. Transcriptional repression mediated by ETO and MTG16 was only slightly strengthened by coexpression of hSIN3B or N-CoR and was dependent on HDAC activity. Our data indicate that ETO family member-mediated oligomerization and repression can be distinct events and that interaction between ETO family members and hSIN3B or N-CoR may not necessarily strengthen transcriptional repression.
authors.affiliation: Department of Hematology, BMC, Lund, Sweden.
authors.forename: André
authors.initials: A
authors.lastname: Olsson
authors.forename: Inge
authors.initials: I
authors.lastname: Olsson
authors.forename: Rakesh Singh
authors.initials: RS
authors.lastname: Dhanda
mesh_terms: D002478:Cells, Cultured; D019281:Dimerization; D015536:Down-Regulation; D006655:Histone Deacetylases / Q000378:metabolism / Q000502:physiology; D006801:Humans; D005810:Multigene Family / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D014162:Transfection; D019076:Transgenes; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C110408:CBFA2T2 myeloid-transforming gene-related protein; C115744:CBFA2T3 protein, human; C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; C082222:RUNX1T1 protein, human; D012097:Repressor Proteins; C492042:SIN3B protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D006655:Histone Deacetylases