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Nuclear PRAS40 couples the Akt/mTORC1 signaling axis to the RPL11-HDM2-p53 nucleolar stress response pathway
- Source :
- Oncogene
- Publication Year :
- 2014
- Publisher :
- Springer Science and Business Media LLC, 2014.
-
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.
- Subjects :
- Ribosomal Proteins
Senescence
Cytoplasm
Cancer Research
senescence
PRAS40
mTORC1
Mechanistic Target of Rapamycin Complex 1
Biology
Article
RPL11
Downregulation and upregulation
Cell Line, Tumor
Genetics
Humans
nucleolar stress
Phosphorylation
Molecular Biology
Protein kinase B
PI3K/AKT/mTOR pathway
Adaptor Proteins, Signal Transducing
Cell Nucleus
TOR Serine-Threonine Kinases
Akt
Proto-Oncogene Proteins c-mdm2
Cell cycle
3. Good health
Cell biology
Multiprotein Complexes
Mutation
mTOR
Cancer research
Tumor Suppressor Protein p53
Signal transduction
Proto-Oncogene Proteins c-akt
HeLa Cells
Signal Transduction
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 34
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....c7988fcb6d649d0cfde48317dca5f9c9