title: Mechanism of transcriptional repression by TEL/RUNX1 fusion protein.
abstract: Human chromosomal translocation t(12;21)(p12;q22) is one of the most frequent rearrangement in human leukemia, and produces the TEL/RUNX1 fusion protein. The TEL/RUNX1 fusion protein creates a transcriptional repressor that interferes in dominant fashion with RUNX1-dependent transactivation. Here, we demonstrate that the repressor activity of TEL/ RUNX1 differs from that of TEL, even though both TEL and TEL/RUNX1 interact with the nuclear hormone co-repressor (N-CoR) and histone deacetylase (mSin3A) in vivo. Co-immunoprecipitation experiments demonstrated that TEL/RUNX1 forms homodimers in vivo, and heterodimerizes with the TEL when the two proteins are expressed together. These interactions require the HLH (helix-loop-helix) region of TEL. Immunoprecipitation and immunofluorescence analysis showed that p300 interacts with TEL/RUNX1 and is sequestered in the cytoplasm by it. These results suggest that the p300-TEL/RUNX1 complex and heterodimerization of TEL/RUNX1 with TEL may be responsible for the ability of TEL/RUNX1 to inhibit RUNX1-mediated transactivation. It appears that loss of TEL function activates a pathway that cooperates with TEL/RUNX1 and sequesters coactivator(s) into nonfunctional complex in the cytoplasm thus inhibiting transcription of target genes.
authors.affiliation: Department of Biology, School of Life Sciences, Research Center for Bioresource and Health, Chungbuk National University, Cheongju 361-763, Korea.
authors.forename: Young Ju
authors.initials: YJ
authors.lastname: Lee
authors.forename: Jae Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Seonghwan
authors.initials: S
authors.lastname: Bae
authors.forename: Seung-Keun
authors.initials: SK
authors.lastname: Rho
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Choe
mesh_terms: D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002881:Chromosomes, Human, Pair 12; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D051548:Histone Acetyltransferases; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism; D007938:Leukemia / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D011500:Protein Synthesis Inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D050880:p300-CBP Transcription Factors; D000097764:ETS Translocation Variant 6 Protein; D000099224:p300-CBP-Associated Factor
chemical_list: D000123:Acetyltransferases; D018797:Cell Cycle Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D006877:Hydroxamic Acids; D015514:Oncogene Proteins, Fusion; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000097764:ETS Translocation Variant 6 Protein; D000099224:p300-CBP-Associated Factor; C493728:RUNX1 protein, human; C488373:TEL-RUNX1 fusion protein, human; C012589:trichostatin A