A RAS-CaMKK?-AMPK?2 pathway promotes senescence by licensing post-translational activation of C/EBP? through a novel 3'UTR mechanism.

ABSTRACT: Oncogene-induced senescence (OIS) is an intrinsic tumor suppression mechanism that requires the p53 and RB pathways and post-translational activation of C/EBP? through the RAS-ERK cascade. We previously reported that in transformed/proliferating cells, C/EBP? 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/EBP? in a low-activity state in tumor cells and thus facilitates senescence bypass. Here we show that C/EBP? 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/EBP? activation and growth arrest. In primary cells, oncogenic RAS triggers a Ca++-CaMKK?-AMPK?2-HuR pathway, independent of AMPK?1, that is essential for C/EBP? activation and OIS. This axis is disrupted in cancer cells through down-regulation of AMPK?2 and CaMKK?. Thus, CaMKK?-AMPK?2 signaling constitutes a key tumor suppressor pathway that activates a novel UPA-cancelling mechanism to unmask the cytostatic and pro-senescence functions of C/EBP?.

SUBMITTER: Basu SK 

PROVIDER: S-EPMC6023738 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature