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

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

Author information

1
1] Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA [2] Graduate Program in Molecular and Systems Pharmacology, Emory University, Atlanta, GA, USA.
2
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.
3
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.

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.

PMID:
24704832
PMCID:
PMC4216640
DOI:
10.1038/onc.2014.91
[Indexed for MEDLINE]
Free PMC Article
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