MOZ-TIF2 inhibits transcription by nuclear receptors and p53 by impairment of CBP function.
Chromosomal rearrangements associated with acute myeloid leukemia (AML) include fusions of the genes encoding the acetyltransferase MOZ or MORF with genes encoding the nuclear receptor coactivator TIF2, p300, or CBP. Here we show that MOZ-TIF2 acts as a dominant inhibitor of the transcriptional activities of CBP-dependent activators such as nuclear receptors and p53. The dominant negative property of MOZ-TIF2 requires the CBP-binding domain (activation domain 1 [AD1]), and coimmunoprecipitation and fluorescent resonance energy transfer experiments show that MOZ-TIF2 interacts with CBP directly in vivo. The CBP-binding domain is also required for the ability of MOZ-TIF2 to extend the proliferative potential of murine bone marrow lineage-negative cells in vitro. We show that MOZ-TIF2 displays an aberrant nuclear distribution and that cells expressing this protein have reduced levels of cellular CBP, leading to depletion of CBP from PML bodies. In summary, our results indicate that disruption of the normal function of CBP and CBP-dependent activators is an important feature of MOZ-TIF2 action in AML.
Kindle
Karin B
KB
School of Pharmacy, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom.
Troke
Philip J F
PJ
Collins
Hilary M
HM
Matsuda
Sachiko
S
Bossi
Daniela
D
Bellodi
Cristian
C
Kalkhoven
Eric
E
Salomoni
Paolo
P
Pelicci
Pier Giuseppe
PG
Minucci
Saverio
S
Heery
David M
DM
D000123:Acetyltransferases / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D031541:Fluorescence Resonance Energy Transfer; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018922:HL-60 Cells; D051548:Histone Acetyltransferases; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D051958:Nuclear Receptor Coactivator 2; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C498001:NCOA2 protein, human; D009687:Nuclear Proteins; D051958:Nuclear Receptor Coactivator 2; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C108712:KAT6A protein, human