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A RAS-CaMKKβ-AMPKα2 pathway promotes senescence by licensing post-translational activation of C/EBPβ through a novel 3′UTR mechanism

Oncogene volume 37, pages 3528–3548 (2018)Cite this article

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Abstract

Oncogene-induced senescence (OIS) is an intrinsic tumor suppression mechanism that requires the p53 and RB pathways and post-translational activation of C/EBPβ through the RAS-ERK cascade. We previously reported that in transformed/proliferating cells, C/EBPβ activation is inhibited by G/U-rich elements (GREs) in its 3′UTR. This mechanism, termed “3′UTR regulation of protein activity” (UPA), maintains C/EBPβ in a low-activity state in tumor cells and thus facilitates senescence bypass. Here we show that C/EBPβ UPA is overridden by AMPK signaling. AMPK activators decrease cytoplasmic levels of the GRE binding protein HuR, which is a key UPA component. Reduced cytoplasmic HuR disrupts 3′UTR-mediated trafficking of Cebpb transcripts to the peripheral cytoplasm—a fundamental feature of UPA—thereby stimulating C/EBPβ activation and growth arrest. In primary cells, oncogenic RAS triggers a Ca++-CaMKKβ-AMPKα2-HuR pathway, independent of AMPKα1, that is essential for C/EBPβ activation and OIS. This axis is disrupted in cancer cells through down-regulation of AMPKα2 and CaMKKβ. Thus, CaMKKβ-AMPKα2 signaling constitutes a key tumor suppressor pathway that activates a novel UPA-cancelling mechanism to unmask the cytostatic and pro-senescence functions of C/EBPβ.

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Acknowledgements

We thank R. Jones for the CA-AMPK vector, N. Bardeesy for Lkb1−/− MEFs, T. Brown for a pan-AMPKα knockdown vector, K. Saylor and N. Martin for animal husbandry and genotyping, and A. Kane (Scientific Publications, Graphics & Media, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research) for preparation of figures. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

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Author notes

  1. Mesfin Gonit

    Present address: Lentigen Tech, Inc., Gaithersburg, MD, USA

  2. Jiji Chen

    Present address: Advanced Imaging and Microscopy Resource, National Institutes of Health, Bethesda, MD, USA

  3. These authors contributed equally: Sandip K. Basu, Mesfin Gonit.

Authors and Affiliations

  1. Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA

    Sandip K. Basu, Mesfin Gonit, Jacqueline Salotti & Peter F. Johnson

  2. Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    Jiji Chen & Atharva Bhat

  3. Laboratory of Genetics, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD, USA

    Myriam Gorospe

  4. INSERM, U1016, Institut Cochin, Paris, 75014, France

    Benoit Viollet

  5. CNRS, UMR8104, Paris, 75014, France

    Benoit Viollet

  6. Université Paris Descartes, Sorbonne Paris Cité, Paris, 75014, France

    Benoit Viollet

  7. Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, USA

    Kevin P. Claffey

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Basu, S.K., Gonit, M., Salotti, J. et al. A RAS-CaMKKβ-AMPKα2 pathway promotes senescence by licensing post-translational activation of C/EBPβ through a novel 3′UTR mechanism. Oncogene 37, 3528–3548 (2018). https://doi.org/10.1038/s41388-018-0190-7

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