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

Immunofluorescence pattern of nucleolar and nuclear membranes. Image by Simon Caulton via Wikimedia Commons.

Immunofluorescence pattern of nucleolar and nuclear membranes. Image by Simon Caulton via Wikimedia Commons

Havel JJ, Li Z, Cheng D, Peng J, Fu H

Oncogene

April 07, 2014

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 ofmTORC1 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 responsepathway 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 PRAS40and identify the PRAS40-RPL11 complex as a promising target for p53-restorative anticancer drug discovery. (Publication Abstract)

Program:
CTD²
Last updated: June 27, 2020