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 qualitycontrol capacity of the cell. Thus, FGF13 may serve as an enabler, allowing cancer cells to evade proteostasis stress triggered by oncogene activation.proteostasis | p53 | miR-504 | FGF13 | ribosomal biogenesis

Knockout of the X‐linkedFgf13in the hypothalamic paraventricular nucleus impairs sympathetic output to brown fat and causes obesity

“…Rather, their best characterized function is as modulators of voltage-gated Na + channels (Na V s) (9), and mutations that affect their Na V modulatory ability have been identified in cardiac arrhythmias and neurologic diseases such as Brugada syndrome, autosomal dominant cerebral ataxia, and epilepsy (10)(11)(12). Beyond regulation of Na V s, FGF13, encoded by Fgf13 on the X chromosome, can regulate other voltage-gated ion channels (13,14) and appears to affect a number of other cellular processes and contribute to physiology or disease states, including cancer (15), hypertrichosis (16), smooth and skeletal muscle cell development (17,18), microtubule stabilization in developing neurons (19), and protection from mechanical stress in cardiomyocytes by regulation of caveolae (20). These observations suggest that the full complement of FGF13 functions is not fully defined.…”

Tumor suppression by p53 involves inhibiting an enabler, FGF13

“…This idea has great translational potential, as such factors can represent novel targets for therapeutic intervention. In PNAS, Bublik et al (1) propose that the fibroblast growth factor 13 (FGF13) protein exerts just such effects during tumorigenesis. Intriguingly, the authors show that these effects are under the transcriptional regulation of the tumor suppressor p53.…”

“…In cells whose proliferation is driven by oncogenic activation, such as mutated Ras, there is an excessive level of protein synthesis that can result in intracellular stress, including increases in unfolded proteins. Bublik et al (1) suggest that the role of FGF13 is to dampen this, thereby allowing tumor cells to proliferate under such stress-inducing conditions. In such a scenario, it is the oncogene, such as Ras, that drives proliferation, whereas the enabler, FGF13, facilitates the survival of such cells.…”

“…A number of studies have shown that disruption of the nucleolus or induction of ribosomal stress leads to an inhibition of Mdm2 activity toward p53, thereby activating p53-dependent cellular responses (16)(17)(18). Because FGF13 is shown by Bublik et al (1) to inhibit ribosomal RNA synthesis, it is intriguing to speculate that there may be an interplay with p53 involving a nucleolus-dependent mechanism. Actinomycin D has been thought to activate p53 because of its effects at also inhibiting ribosomal RNA synthesis (16,17).…”

“…Much of the data generated by Bublik et al (1) has come from studies in cell culture. It remains to be seen how relevant these findings will be either in vivo or in human tumor samples.…”