title: Regulatory module involving FGF13, miR-504, and p53 regulates ribosomal biogenesis and supports cancer cell survival.
abstract: The microRNA miR-504 targets TP53 mRNA encoding the p53 tumor suppressor. miR-504 resides within the fibroblast growth factor 13 (FGF13) gene, which is overexpressed in various cancers. We report that the FGF13 locus, comprising FGF13 and miR-504, is transcriptionally repressed by p53, defining an additional negative feedback loop in the p53 network. Furthermore, we show that FGF13 1A is a nucleolar protein that represses ribosomal RNA transcription and attenuates protein synthesis. Importantly, in cancer cells expressing high levels of FGF13, the depletion of FGF13 elicits increased proteostasis stress, associated with the accumulation of reactive oxygen species and apoptosis. Notably, stepwise neoplastic transformation is accompanied by a gradual increase in FGF13 expression and increased dependence on FGF13 for survival ("nononcogene addiction"). Moreover, FGF13 overexpression enables cells to cope more effectively with the stress elicited by oncogenic Ras protein. We propose that, in cells in which activated oncogenes drive excessive protein synthesis, FGF13 may favor survival by maintaining translation rates at a level compatible with the protein quality-control capacity of the cell. Thus, FGF13 may serve as an enabler, allowing cancer cells to evade proteostasis stress triggered by oncogene activation.
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Débora R
authors.initials: DR
authors.lastname: Bublik
authors.affiliation: Department of Molecular Medicine and Biotechnology, School of Medicine, University of Rijeka, Rijeka 51000, Croatia.
authors.forename: Slađana
authors.initials: S
authors.lastname: Bursać
authors.affiliation: Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Sheffer
authors.affiliation: Department of Molecular Medicine and Biotechnology, School of Medicine, University of Rijeka, Rijeka 51000, Croatia.
authors.forename: Ines
authors.initials: I
authors.lastname: Oršolić
authors.affiliation: de Botton Institute for Protein Profiling, The Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Tali
authors.initials: T
authors.lastname: Shalit
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Ohad
authors.initials: O
authors.lastname: Tarcic
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Kotler
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Odelia
authors.initials: O
authors.lastname: Mouhadeb
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Yonit
authors.initials: Y
authors.lastname: Hoffman
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Gilad
authors.initials: G
authors.lastname: Fuchs
authors.affiliation: de Botton Institute for Protein Profiling, The Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Yishai
authors.initials: Y
authors.lastname: Levin
authors.affiliation: Department of Molecular Medicine and Biotechnology, School of Medicine, University of Rijeka, Rijeka 51000, Croatia.
authors.forename: Siniša
authors.initials: S
authors.lastname: Volarević
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel; moshe.oren@weizmann.ac.il.
authors.forename: Moshe
authors.initials: M
authors.lastname: Oren
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C550379:MIRN504 microRNA, human; D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C108111:fibroblast growth factor 13; D005346:Fibroblast Growth Factors
keywords: FGF13; miR-504; p53; proteostasis; ribosomal biogenesis