The MN1-TEL myeloid leukemia-associated fusion protein has a dominant-negative effect on RAR-RXR-mediated transcription.
The translocation t(12;22)(p13;q11) creates an MN1-TEL fusion gene leading to acute myeloid leukemia. MN1 is a transcription coactivator of the retinoic acid and vitamin D receptors, and TEL (ETV6) is a member of the E26-transformation-specific family of transcription factors. In MN1-TEL, the transactivating domains of MN1 are combined with the DNA-binding domain of TEL. We show that MN1-TEL inhibits retinoic acid receptor (RAR)-mediated transcription, counteracts coactivators such as p160 and p300, and acts as a dominant-negative mutant of MN1. Compared to MN1, the same transactivation domains in MN1-TEL are poorly stimulated by p160, p300 or histone deacetylase inhibitors, indicating that the block of RAR-mediated transcription by MN1-TEL is caused by dysfunctional transactivation domains rather than by recruitment of corepressors. The mechanism leading to myeloid leukemia in t(12;22) thus differs from the translocations that involve RAR itself.
van Wely
K H M
KH
Department of Pathology, Josephine Nefkens Institute, Erasmus MC, CA Rotterdam, The Netherlands.
Meester-Smoor
M A
MA
Janssen
M J F W
MJ
Aarnoudse
A-J
AJ
Grosveld
G C
GC
Zwarthoff
E C
EC
D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D004268:DNA-Binding Proteins; D050881:E1A-Associated p300 Protein / Q000502:physiology; D004791:Enzyme Inhibitors; D005799:Genes, Dominant; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins / Q000502:physiology; D029543:Nucleocytoplasmic Transport Proteins / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D016601:RNA-Binding Proteins; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D047488:Retinoid X Receptors / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; C417770:MN1-TEL fusion protein, human; C491719:MYBBP1A protein, human; D009687:Nuclear Proteins; D029543:Nucleocytoplasmic Transport Proteins; D015514:Oncogene Proteins, Fusion; D016601:RNA-Binding Proteins; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human