| Author |
Fuchs, Gilad Sheffer, Michal Kotler, Eran Levin, Yishai Oren, Moshe Shalit, Tali Bursac, Sladana Hoffman, Yonit Volarevic, Sinisa Orsolic, Ines Bublik, Débora R. Tarcic, Ohad Mouhadeb, Odelia |
| Description |
Author Affiliation: Bublik DR ( Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.); Bursac S ( Department of Molecular Medicine and Biotechnology, School of Medicine, University of Rijeka, Rijeka 51000, Croatia.); Sheffer M ( Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot 76100, Israel.); Orsolic I ( Department of Molecular Medicine and Biotechnology, School of Medicine, University of Rijeka, Rijeka 51000, Croatia.); Shalit T ( de Botton Institute for Protein Profiling, The Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 76100, Israel.); Tarcic O ( Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.); Kotler E ( Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.); Mouhadeb O ( Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.); Hoffman Y ( Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.); Fuchs G ( Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.); Levin Y ( de Botton Institute for Protein Profiling, The Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 76100, Israel.); Volarevic S ( Department of Molecular Medicine and Biotechnology, School of Medicine, University of Rijeka, Rijeka 51000, Croatia.); Oren M ( Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel); |
| 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. |
