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Acute Leukemias

The downregulation of onzin expression by PKCɛ-ERK2 signaling and its potential role in AML cell differentiation

Leukemia volume 24, pages 544–551 (2010)Cite this article

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Abstract

Onzin is a small, novel, and highly conserved protein with unique structure and tissue-restricted expression. The regulation of its expression and biological roles remain greatly elusive. Here, we provide the first demonstration that onzin expression is significantly downregulated during differentiation induction of acute myeloid leukemic (AML) cell lines and primary cells by all-trans retinoic acid (ATRA) and especially by phorbol 12-myristate 13-acetate (PMA). Applying chemical inhibitions, RNA interferences, and transfected expressions of dominant negative mutants or constitutive catalytic forms of the related kinases, we show that protein kinase C-ɛ (PKCɛ)-extracellular signal-regulated protein kinase 2 (ERK2) signaling axis is required for PMA-induced downregulation of onzin expression. The ectopic expression of onzin partially inhibits PMA-induced monocytic differentiation of AML cells, whereas suppression of onzin by specific short hairpin RNAs enhances PMA-induced differentiation to a degree. Furthermore, onzin partially inhibits the transcriptional activity of hematopoiesis-related important transcription factor PU.1 via their interaction. Taken together, our results show that PMA downregulates onzin expression through PKCɛ-ERK2 signaling pathway, which favors monocytic differentiation of leukemic cells.

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Acknowledgements

We thank Dr Jae-Won Soh for generously providing plasmids pHACB-PKCβII-DN, pHACE-PKCɛ-DN, pHACB-PKCβII-CAT, and pHACE-PKCɛ-CAT. This work is supported in part by grants from the Ministry of Science and Technology (2009CB918500), National Natural Science Foundation of China (90813034), Chinese Academy of Sciences (KSCX2-YW-R-097), and Science and Technology Commission of Shanghai (08JC1413700). SF WU is a PhD candidate at Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences, and this work is submitted in partial fulfillment of the requirement for the PhD. Dr GQ Chen is supported by Shanghai Ling-Jun Talent Program.

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  1. S-F Wu and Y Huang: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Health Science, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences-Shanghai Jiaotong University School of Medicine (SJTU-SM), Shanghai, China

    S-F Wu, J-K Hou, T-T Yuan, J Zhang & G-Q Chen

  2. Department of Pathophysiology, Shanghai Universities E-Institute for Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, SJTU-SM, Shanghai, China

    Y Huang, C-X Zhou & G-Q Chen

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Correspondence to G-Q Chen.

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Wu, SF., Huang, Y., Hou, JK. et al. The downregulation of onzin expression by PKCɛ-ERK2 signaling and its potential role in AML cell differentiation. Leukemia 24, 544–551 (2010). https://doi.org/10.1038/leu.2009.280

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