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bioRxiv · 10.1101/2022.03.29.486281

3'UTR-directed, kinase proximal mRNA decay inhibits C/EBPβ phosphorylation/activation to suppress senescence in tumor cells

Salotti, J.·Karim, B.·Misra, S.·Hu, L.·Basu, S.·Martin, N.·Luke, B.·Saylor, K.·Andresson, T.·Scheiblin, D. A.·Lockett, S.·Tessarollo, L.·Johnson, P. F.
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Abstract

C/EBP{beta} is a potent regulator of oncogene-induced senescence (OIS) and the SASP. C/EBP{beta} is post-translationally activated in OIS cells by the effector kinases ERK1/2 and CK2. However, in tumor cells C/EBP{beta} activation is suppressed by its 3UTR. 3'UTR regulation of protein activity (UPA) requires a G/U-rich element (GRE) and its cognate binding protein, HuR. These components segregate CEBPB transcripts away from a perinuclear compartment harboring ERK1/2 and CK2, restricting C/EBP{beta} from its activating kinases. We report here that the mRNA decay proteins UPF1 and Staufen1/2 are essential UPA factors enriched within the perinuclear cytoplasm. STAU1/2 and UPF1 overlap with CK2 on perinuclear signaling endosomes where they promote localized CEBPB mRNA decay. UPF1 or STAU1/2 depletion in tumor cells increased CEBPB transcripts adjacent to CK2 foci, coinciding with C/EBP{beta} activation and senescence. The GRE and an adjacent STAU binding site independently suppress C/EBP{beta}-mediated senescence, while a distinct 3UTR region inhibits its SASP-inducing activity. KrasG12D-driven lung tumors in mice carrying a Cebpb GRE deletion rarely progressed to malignant adenocarcinomas, demonstrating the importance of UPA to enable tumor progression in vivo. Thus, kinase-proximal mRNA decay is a novel mechanism that inhibits C/EBP{beta} activation in tumor cells to facilitate senescence bypass.

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Salotti, J., Karim, B., Misra, S., Hu, L., Basu, S., Martin, N., Luke, B., Saylor, K., Andresson, T., Scheiblin, D. A., Lockett, S., Tessarollo, L., Johnson, P. F.. 2022-03-29. 3'UTR-directed, kinase proximal mRNA decay inhibits C/EBPβ phosphorylation/activation to suppress senescence in tumor cells. https://doi.org/10.1101/2022.03.29.486281

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