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ERK-mediated NELF-A phosphorylation promotes transcription elongation of immediate-early genes by releasing promoter-proximal pausing of RNA polymerase II

Author

Listed:
  • Seina Ohe

    (The University of Tokyo
    The University of Tokyo)

  • Yuji Kubota

    (The University of Tokyo)

  • Kiyoshi Yamaguchi

    (The University of Tokyo)

  • Yusuke Takagi

    (The University of Tokyo)

  • Junichiro Nashimoto

    (The University of Tokyo)

  • Hiroko Kozuka-Hata

    (The University of Tokyo)

  • Masaaki Oyama

    (The University of Tokyo)

  • Yoichi Furukawa

    (The University of Tokyo)

  • Mutsuhiro Takekawa

    (The University of Tokyo
    The University of Tokyo
    The University of Tokyo)

Abstract

Growth factor-induced, ERK-mediated induction of immediate-early genes (IEGs) is crucial for cell growth and tumorigenesis. Although IEG expression is mainly regulated at the level of transcription elongation by RNA polymerase-II (Pol-II) promoter-proximal pausing and its release, the role of ERK in this process remains unknown. Here, we identified negative elongation factor (NELF)-A as an ERK substrate. Upon growth factor stimulation, ERK phosphorylates NELF-A, which dissociates NELF from paused Pol-II at the promoter-proximal regions of IEGs, allowing Pol-II to resume elongation and produce full-length transcripts. Furthermore, we found that in cancer cells, PP2A efficiently dephosphorylates NELF-A, thereby preventing aberrant IEG expression induced by ERK-activating oncogenes. However, when PP2A inhibitor proteins are overexpressed, as is frequently observed in cancers, decreased PP2A activity combined with oncogene-mediated ERK activation conspire to induce NELF-A phosphorylation and IEG upregulation, resulting in tumor progression. Our data delineate previously unexplored roles of ERK and PP2A inhibitor proteins in carcinogenesis.

Suggested Citation

  • Seina Ohe & Yuji Kubota & Kiyoshi Yamaguchi & Yusuke Takagi & Junichiro Nashimoto & Hiroko Kozuka-Hata & Masaaki Oyama & Yoichi Furukawa & Mutsuhiro Takekawa, 2022. "ERK-mediated NELF-A phosphorylation promotes transcription elongation of immediate-early genes by releasing promoter-proximal pausing of RNA polymerase II," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35230-4
    DOI: 10.1038/s41467-022-35230-4
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    References listed on IDEAS

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