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Nuclear PRAS40 couples the Akt/mTORC1 signaling axis to the RPL11-HDM2-p53 nucleolar stress response pathway

Oncogene volume 34, pages 1487–1498 (2015)Cite this article

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Abstract

The ribosomal protein (RP)-HDM2-p53 pathway has been shown to have key roles in oncogene-induced apoptosis and senescence, but the mechanism regulating this pathway remains elusive. The proline-rich Akt substrate of 40 kDa (PRAS40) has recently been identified as a binding partner and inhibitor of the mechanistic (formerly referred to as mammalian) target of rapamycin complex 1 (mTORC1). Although other inhibitors of mTORC1 are known tumor suppressors, PRAS40 promotes cell survival and tumorigenesis. Here we demonstrate that Akt- and mTORC1-mediated phosphorylation of PRAS40 at T246 and S221, respectively, promotes nuclear-specific association of PRAS40 with ribosomal protein L11 (RPL11). Importantly, silencing of PRAS40 induces upregulation of p53 in a manner dependent on RPL11. This effect is rescued by wild-type PRAS40, but not by the RPL11-binding-null PRAS40T246A mutant. We found that PRAS40 negatively regulates the RPL11-HDM2-p53 nucleolar stress response pathway and suppresses induction of p53-mediated cellular senescence. This work identifies nuclear PRAS40 as a dual-input signaling checkpoint that links cell growth and proliferation to inhibition of cellular senescence. These findings may help to explain the protumorigenic effect of PRAS40 and identify the PRAS40–RPL11 complex as a promising target for p53-restorative anticancer drug discovery.

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Acknowledgements

This research was supported in part by NIH predoctoral NRSA F31NS067844 and training grant T32GM008602 (to JJH), NIH U01CA168449 and a Georgia Cancer Coalition Award (to HF) and the Emory University Integrated Cellular Imaging Microscopy Core of the Emory Neuroscience NINDS Core Facilities Grant P30NS055077. We thank Shannon Elf for assistance with plasmid generation, and Anita Corbett and Maureen Powers for helpful discussions.

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  1. D Cheng & J Peng

    Present address: 4Current Address: Departments of Structural Biology and Developmental Neurobiology, St Jude Children’s Research Hospital, Memphis, TN 38105, USA.,

Authors and Affiliations

  1. Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA

    J J Havel, Z Li & H Fu

  2. Graduate Program in Molecular and Systems Pharmacology, Emory University, Atlanta, GA, USA

    J J Havel

  3. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA

    D Cheng & J Peng

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Havel, J., Li, Z., Cheng, D. et al. Nuclear PRAS40 couples the Akt/mTORC1 signaling axis to the RPL11-HDM2-p53 nucleolar stress response pathway. Oncogene 34, 1487–1498 (2015). https://doi.org/10.1038/onc.2014.91

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