MOZ and MOZ-CBP cooperate with NF-kappaB to activate transcription from NF-kappaB-dependent promoters

• Published in: Experimental hematology Vol. 35; no. 12; pp. 1782 - 1792
• Main Authors: Chan, Edward M, Chan, Rebecca J, Comer, Elisha M, Goulet, 3rd, Robert J, Crean, Colin D, Brown, Zachary D, Fruehwald, Amy M, Yang, Zhenyun, Boswell, H Scott, Nakshatri, Harikrishna, Gabig, Theodore G
• Format: Journal Article
• Language: English
• Published: Netherlands 01-12-2007
• Subjects: Base Sequence; Cell Line; DNA Primers; Humans; Immunoprecipitation; Interleukin-8 - genetics; NF-kappa B - metabolism; Oncogene Proteins, Fusion - physiology; Promoter Regions, Genetic; Transcription, Genetic
• ISSN: 0301-472X

Monocytic zinc finger (MOZ) maintains hematopoietic stem cells and, upon fusion to the coactivator CREB-binding protein (CBP), induces acute myeloid leukemia (AML). Leukemic stem cells in AML often exhibit excessive signal-dependent activity of the transcription factor nuclear factor (NF)-kappaB. Because aberrant interaction between NF-kappaB and coactivators represents an alternative mechanism for enhancing NF-kappaB activity, we evaluated whether MOZ and MOZ-CBP cooperate with NF-kappaB to activate transcription from NF-kappaB-dependent promoters.
The ability of MOZ, MOZ mutants, and MOZ-CBP to enhance expression of NF-kappaB-dependent promoters was tested in reporter studies. The interaction between MOZ and NF-kappaB was evaluated by both coimmunoprecipitation and glutathione S-transferase pulldown assays.
MOZ activates transcription from the NF-kappaB-dependent interleukin-8 promoter; interestingly, this effect is markedly enhanced by CBP. Although MOZ has less potent transcriptional activity than MOZ-CBP, both proteins cooperate with steroid receptor coactivator-1 to activate transcription. MOZ also induces multiple NF-kappaB-dependent viral promoters. Importantly, MOZ associates in a protein complex with the p65 subunit of NF-kappaB and interacts directly with p65 in vitro. Transcriptional activity of MOZ requires its C-terminal domain, which is absent from MOZ-CBP, indicating that the transcriptional activity of MOZ-CBP derives from its CBP sequence.
MOZ interacts with the p65 subunit of NF-kappaB and enhances expression of NF-kappaB-dependent promoters. The more potent transcriptional activity of MOZ-CBP derives from its CBP sequence. Thus, interaction between NF-kappaB and MOZ-CBP may play an important role in the pathogenesis of certain acute myeloid leukemias.