The MN1 oncoprotein synergizes with coactivators RAC3 and p300 in RAR-RXR-mediated transcription.
The t(12;22) creates an MN1-TEL fusion gene leading to acute myeloid leukemia. The fusion partner TEL (ETV6) is a member of the ETS family of transcription factors. The nature of the other fusion partner, MN1, has not been investigated in detail until now. We recently described that MN1 activates the transcription activity of the moloney sarcoma virus long terminal repeat, indicating that this protein itself may act as a transcription factor. We show here that MN1 comprises multiple transcription activating domains. A search for a bound DNA sequence revealed that MN1 has affinity for retinoic acid responsive elements. A DR5 retinoic acid responsive element was observed in the LTR. The combination of MN1 and ligand-activated retinoic acid receptor leads to a synergistic induction of expression directed by the LTR. Cotransfection of MN1 with RAC3 or p300, known coactivators of retinoic acid receptors, leads to a further synergistic induction of transcription. In addition, the effect of MN1 can be inhibited by the wild-type adenovirus ElA protein that inhibits p300 function, but not by an E1A mutant lacking the p300-binding site. GAL4-MN1-mediated transcription can be enhanced directly by RAC3 and p300. Taken together, our results indicate that MN1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate RAR/RXR-mediated transcription through interaction with p160 and p300.
van Wely
Karel H M
KH
Department of Pathology, Erasmus University, Rotterdam, The Netherlands.
Molijn
Anco C
AC
Buijs
Arjan
A
Meester-Smoor
Magda A
MA
Aarnoudse
Albert Jan
AJ
Hellemons
Anita
A
den Besten
Pim
P
Grosveld
Gerard C
GC
Zwarthoff
Ellen C
EC
D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000502:physiology; D004268:DNA-Binding Proteins; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000502:physiology*; D029543:Nucleocytoplasmic Transport Proteins; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D016601:RNA-Binding Proteins; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000502:physiology*
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C417770:MN1-TEL fusion protein, human; C491719:MYBBP1A protein, human; D009687:Nuclear Proteins; D029543:Nucleocytoplasmic Transport Proteins; D015514:Oncogene Proteins, Fusion; C411563:RAC3 protein, human; D016601:RNA-Binding Proteins; D018168:Receptors, Retinoic Acid; D015534:Trans-Activators; D014157:Transcription Factors; D020744:rac GTP-Binding Proteins