| First Author | Basu SK | Year | 2018 |
| Journal | Oncogene | Volume | 37 |
| Issue | 26 | Pages | 3528-3548 |
| PubMed ID | 29563610 | Mgi Jnum | J:263999 |
| Mgi Id | MGI:6193285 | Doi | 10.1038/s41388-018-0190-7 |
| Citation | Basu SK, et al. (2018) A RAS-CaMKKbeta-AMPKalpha2 pathway promotes senescence by licensing post-translational activation of C/EBPbeta through a novel 3'UTR mechanism. Oncogene 37(26):3528-3548 |
| abstractText | Oncogene-induced senescence (OIS) is an intrinsic tumor suppression mechanism that requires the p53 and RB pathways and post-translational activation of C/EBPbeta through the RAS-ERK cascade. We previously reported that in transformed/proliferating cells, C/EBPbeta activation is inhibited by G/U-rich elements (GREs) in its 3'UTR. This mechanism, termed "3'UTR regulation of protein activity" (UPA), maintains C/EBPbeta in a low-activity state in tumor cells and thus facilitates senescence bypass. Here we show that C/EBPbeta UPA is overridden by AMPK signaling. AMPK activators decrease cytoplasmic levels of the GRE binding protein HuR, which is a key UPA component. Reduced cytoplasmic HuR disrupts 3'UTR-mediated trafficking of Cebpb transcripts to the peripheral cytoplasm-a fundamental feature of UPA-thereby stimulating C/EBPbeta activation and growth arrest. In primary cells, oncogenic RAS triggers a Ca(++)-CaMKKbeta-AMPKalpha2-HuR pathway, independent of AMPKalpha1, that is essential for C/EBPbeta activation and OIS. This axis is disrupted in cancer cells through down-regulation of AMPKalpha2 and CaMKKbeta. Thus, CaMKKbeta-AMPKalpha2 signaling constitutes a key tumor suppressor pathway that activates a novel UPA-cancelling mechanism to unmask the cytostatic and pro-senescence functions of C/EBPbeta. |
