FGFR1-Activated Translation of WNT Pathway Components with Structured 5' UTRs Is Vulnerable to Inhibition of EIF4A-Dependent Translation Initiation

Cancer Research
Tuan M NguyenJeffrey M Rosen

Abstract

Cooperativity between WNT and FGF signaling is well documented in embryonic development and cancer progression, but the molecular mechanisms underlying this cross-talk remain elusive. In this study, we interrogated the dynamics of RNA levels, ribosome occupancy, and protein expression as a function of inducible FGF signaling in mouse mammary glands with constitutive WNT hyperactivation. Multiomics correlation analysis revealed a substantial discrepancy between RNA and ribosome occupancy levels versus protein levels. However, this discrepancy decreased as cells became premalignant and dynamically responded to FGF signaling, implicating the importance of stringent gene regulation in nontransformed cells. Analysis of individual genes demonstrated that acute FGF hyperactivation increased translation of many stem cell self-renewal regulators, including WNT signaling components, and decreased translation of genes regulating cellular senescence. WNT pathway components translationally upregulated by FGF signaling had long and structured 5' UTRs with a high frequency of polypurine sequences, several of which harbored (CGG)4 motifs that can fold into either stable G-quadruplexes or other stable secondary structures. The FGF-mediated incr...Continue Reading

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Citations

Sep 7, 2018·Journal of Cell Science·Lucas C ReinekeJoel R Neilson
Dec 22, 2019·Nucleic Acids Research·Tuan M NguyenJeffrey M Rosen
Aug 23, 2020·International Journal of Molecular Sciences·Chen ShenDavid J Robbins
Jun 12, 2020·RNA Biology·Tuan M NguyenJeffrey M Rosen
Jul 17, 2021·Cell Chemical Biology·Ashley E ModellAmit Choudhary
Jul 18, 2021·Nature Reviews. Molecular Cell Biology·James A SabaFiona M Watt
May 3, 2019·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Xiaohong XuYi Wang

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