title: MOZ and MOZ-CBP cooperate with NF-kappaB to activate transcription from NF-kappaB-dependent promoters.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Walther Oncology Center, Indianapolis, IN, USA. chanem@lilly.com
authors.forename: Edward M
authors.initials: EM
authors.lastname: Chan
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Chan
authors.forename: Elisha M
authors.initials: EM
authors.lastname: Comer
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Goulet
authors.forename: Colin D
authors.initials: CD
authors.lastname: Crean
authors.forename: Zachary D
authors.initials: ZD
authors.lastname: Brown
authors.forename: Amy M
authors.initials: AM
authors.lastname: Fruehwald
authors.forename: Zhenyun
authors.initials: Z
authors.lastname: Yang
authors.forename: H Scott
authors.initials: HS
authors.lastname: Boswell
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Nakshatri
authors.forename: Theodore G
authors.initials: TG
authors.lastname: Gabig
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D006801:Humans; D047468:Immunoprecipitation; D016209:Interleukin-8 / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic
chemical_list: D017931:DNA Primers; D016209:Interleukin-8; C470260:MOZ-CBP fusion protein, human; D016328:NF-kappa B; D015514:Oncogene Proteins, Fusion