PRAS40 promotes NF-κB transcriptional activity through association with p65.

PRAS40 has been shown to have a crucial role in the repression of mammalian target of rapamycin (mTOR). Nonetheless, PRAS40 appears to have an oncogenic function in cancer cells. Whether PRAS40 mediates signaling independent of mTOR inhibition in cancer cells remains elusive. Here PRAS40 overexpression in lung adenocarcinoma and cutaneous melanoma was significantly correlated to worse prognosis. And we identified an unexpected role for PRAS40 in the regulation of nuclear factor (NF)-κB signaling. P65, a subunit of the NF-κB transcription factor complex, was confirmed to associate with PRAS40 by glutathione S-transferase co-precipitation. Importantly, we found that PRAS40 can enhance NF-κB transcriptional activity in a manner dependent upon PRAS40-P65 association. Furthermore, we found that a small p65-derived peptide can disrupt the PRAS40-P65 association and significantly decrease NF-κB transcriptional activity. These findings may help elucidate the pleiotropic functions of PRAS40 in cells and suggest a novel therapeutic strategy in cancer patients with high expression of PRAS40 and NF-κB.

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

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.