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NGF inhibits human leukemia proliferation by downregulating cyclin A1 expression through promoting acinus/CtBP2 association

Oncogene volume 28, pages 3825–3836 (2009)Cite this article

Abstract

Cyclin A1 is essential for leukemia progression, and its expression is tightly regulated by acinus, a nuclear speckle protein. However, the molecular mechanism of how acinus mediates cyclin A1 expression remains elusive. Here we show that transcription corepressor CtBP2 directly binds acinus, which is regulated by nerve growth factor (NGF), inhibiting its stimulatory effect on cyclin A1, but not cyclin A2, expression in leukemia. NGF, a cognate ligand for the neurotrophic receptor TrkA, promotes the interaction between CtBP2 and acinus through triggering acinus phosphorylation by Akt. Overexpression of CtBP2 diminishes cyclin A1 transcription, whereas depletion of CtBP2 abolishes NGF's suppressive effect on cyclin A1 expression. Strikingly, gambogic amide, a newly identified TrkA agonist, potently represses cyclin A1 expression, thus blocking K562 cell proliferation. Moreover, gambogic amide ameliorates the leukemia progression in K562 cells inoculated nude mice. Hence, NGF downregulates cyclin A1 expression through escalating CtBP2/acinus complex formation, and gambogic amide might be useful for human leukemia treatment.

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Acknowledgements

This work is supported by a grant from NIH (RO1 NS060680) to K Ye. We thank Dr G Chinnadurai (Saint Louis University Health Sciences Center) for GST-CtBP1 plasmid.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA

    C B Chan, X Liu, S -W Jang, I Williams & K Ye

  2. Department of Medicine, Faculty of Medicine, National University of Singapore, Singapore

    S I-H Hsu

  3. Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA

    S Kang & J Chen

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  1. C B Chan
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Correspondence to K Ye.

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Chan, C., Liu, X., Jang, SW. et al. NGF inhibits human leukemia proliferation by downregulating cyclin A1 expression through promoting acinus/CtBP2 association. Oncogene 28, 3825–3836 (2009). https://doi.org/10.1038/onc.2009.236

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