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

Oncogene. 2015 Mar 19;34(12):1487-98. doi: 10.1038/onc.2014.91. Epub 2014 Apr 7.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Cell Line, Tumor
  • Cell Nucleus / metabolism*
  • Cytoplasm / metabolism
  • HeLa Cells
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Multiprotein Complexes / metabolism*
  • Mutation
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Ribosomal Proteins / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • AKT1S1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Multiprotein Complexes
  • Ribosomal Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • ribosomal protein L11
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt