Mechanism of transcriptional repression by TEL/RUNX1 fusion protein.
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.
Lee
Young Ju
YJ
Department of Biology, School of Life Sciences, Research Center for Bioresource and Health, Chungbuk National University, Cheongju 361-763, Korea.
Kim
Jae Hyun
JH
Bae
Seonghwan
S
Rho
Seung-Keun
SK
Choe
Soo Young
SY
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
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