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

Edward M. Chan, Rebecca Chan, Elisha M. Comer, Robert J. Goulet, Colin D. Crean, Zachary D. Brown, Amy M. Fruehwald, Zhenyun Yang, H. Boswell, Harikrishna Nakshatri, Theodore G. Gabig

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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)-κB. Because aberrant interaction between NF-κB and coactivators represents an alternative mechanism for enhancing NF-κB activity, we evaluated whether MOZ and MOZ-CBP cooperate with NF-κB to activate transcription from NF-κB-dependent promoters. Methods: The ability of MOZ, MOZ mutants, and MOZ-CBP to enhance expression of NF-κB-dependent promoters was tested in reporter studies. The interaction between MOZ and NF-κB was evaluated by both coimmunoprecipitation and glutathione S-transferase pulldown assays. Results: MOZ activates transcription from the NF-κB-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-κB-dependent viral promoters. Importantly, MOZ associates in a protein complex with the p65 subunit of NF-κB 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-κB and enhances expression of NF-κB-dependent promoters. The more potent transcriptional activity of MOZ-CBP derives from its CBP sequence. Thus, interaction between NF-κB and MOZ-CBP may play an important role in the pathogenesis of certain acute myeloid leukemias.

Original languageEnglish
Pages (from-to)1782-1792
Number of pages11
JournalExperimental Hematology
Volume35
Issue number12
DOIs
StatePublished - Dec 2007

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CREB-Binding Protein
Zinc Fingers
Transcription Factors
Acute Myeloid Leukemia
Nuclear Receptor Coactivator 1

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

Cite this

Chan, E. M., Chan, R., Comer, E. M., Goulet, R. J., Crean, C. D., Brown, Z. D., ... Gabig, T. G. (2007). MOZ and MOZ-CBP cooperate with NF-κB to activate transcription from NF-κB-dependent promoters. Experimental Hematology, 35(12), 1782-1792. https://doi.org/10.1016/j.exphem.2007.07.015

MOZ and MOZ-CBP cooperate with NF-κB to activate transcription from NF-κB-dependent promoters. / Chan, Edward M.; Chan, Rebecca; Comer, Elisha M.; Goulet, Robert J.; Crean, Colin D.; Brown, Zachary D.; Fruehwald, Amy M.; Yang, Zhenyun; Boswell, H.; Nakshatri, Harikrishna; Gabig, Theodore G.

In: Experimental Hematology, Vol. 35, No. 12, 12.2007, p. 1782-1792.

Research output: Contribution to journalArticle

Chan, EM, Chan, R, Comer, EM, Goulet, RJ, Crean, CD, Brown, ZD, Fruehwald, AM, Yang, Z, Boswell, H, Nakshatri, H & Gabig, TG 2007, 'MOZ and MOZ-CBP cooperate with NF-κB to activate transcription from NF-κB-dependent promoters', Experimental Hematology, vol. 35, no. 12, pp. 1782-1792. https://doi.org/10.1016/j.exphem.2007.07.015
Chan, Edward M. ; Chan, Rebecca ; Comer, Elisha M. ; Goulet, Robert J. ; Crean, Colin D. ; Brown, Zachary D. ; Fruehwald, Amy M. ; Yang, Zhenyun ; Boswell, H. ; Nakshatri, Harikrishna ; Gabig, Theodore G. / MOZ and MOZ-CBP cooperate with NF-κB to activate transcription from NF-κB-dependent promoters. In: Experimental Hematology. 2007 ; Vol. 35, No. 12. pp. 1782-1792.
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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)-κB. Because aberrant interaction between NF-κB and coactivators represents an alternative mechanism for enhancing NF-κB activity, we evaluated whether MOZ and MOZ-CBP cooperate with NF-κB to activate transcription from NF-κB-dependent promoters. Methods: The ability of MOZ, MOZ mutants, and MOZ-CBP to enhance expression of NF-κB-dependent promoters was tested in reporter studies. The interaction between MOZ and NF-κB was evaluated by both coimmunoprecipitation and glutathione S-transferase pulldown assays. Results: MOZ activates transcription from the NF-κB-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-κB-dependent viral promoters. Importantly, MOZ associates in a protein complex with the p65 subunit of NF-κB 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-κB and enhances expression of NF-κB-dependent promoters. The more potent transcriptional activity of MOZ-CBP derives from its CBP sequence. Thus, interaction between NF-κB and MOZ-CBP may play an important role in the pathogenesis of certain acute myeloid leukemias.",
author = "Chan, {Edward M.} and Rebecca Chan and Comer, {Elisha M.} and Goulet, {Robert J.} and Crean, {Colin D.} and Brown, {Zachary D.} and Fruehwald, {Amy M.} and Zhenyun Yang and H. Boswell and Harikrishna Nakshatri and Gabig, {Theodore G.}",
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AU - Chan, Edward M.

AU - Chan, Rebecca

AU - Comer, Elisha M.

AU - Goulet, Robert J.

AU - Crean, Colin D.

AU - Brown, Zachary D.

AU - Fruehwald, Amy M.

AU - Yang, Zhenyun

AU - Boswell, H.

AU - Nakshatri, Harikrishna

AU - Gabig, Theodore G.

PY - 2007/12

Y1 - 2007/12

N2 - 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)-κB. Because aberrant interaction between NF-κB and coactivators represents an alternative mechanism for enhancing NF-κB activity, we evaluated whether MOZ and MOZ-CBP cooperate with NF-κB to activate transcription from NF-κB-dependent promoters. Methods: The ability of MOZ, MOZ mutants, and MOZ-CBP to enhance expression of NF-κB-dependent promoters was tested in reporter studies. The interaction between MOZ and NF-κB was evaluated by both coimmunoprecipitation and glutathione S-transferase pulldown assays. Results: MOZ activates transcription from the NF-κB-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-κB-dependent viral promoters. Importantly, MOZ associates in a protein complex with the p65 subunit of NF-κB 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-κB and enhances expression of NF-κB-dependent promoters. The more potent transcriptional activity of MOZ-CBP derives from its CBP sequence. Thus, interaction between NF-κB and MOZ-CBP may play an important role in the pathogenesis of certain acute myeloid leukemias.

AB - 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)-κB. Because aberrant interaction between NF-κB and coactivators represents an alternative mechanism for enhancing NF-κB activity, we evaluated whether MOZ and MOZ-CBP cooperate with NF-κB to activate transcription from NF-κB-dependent promoters. Methods: The ability of MOZ, MOZ mutants, and MOZ-CBP to enhance expression of NF-κB-dependent promoters was tested in reporter studies. The interaction between MOZ and NF-κB was evaluated by both coimmunoprecipitation and glutathione S-transferase pulldown assays. Results: MOZ activates transcription from the NF-κB-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-κB-dependent viral promoters. Importantly, MOZ associates in a protein complex with the p65 subunit of NF-κB 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-κB and enhances expression of NF-κB-dependent promoters. The more potent transcriptional activity of MOZ-CBP derives from its CBP sequence. Thus, interaction between NF-κB and MOZ-CBP may play an important role in the pathogenesis of certain acute myeloid leukemias.

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