Absence of nucleolar disruption after impairment of 40S ribosome biogenesis reveals an rpL11-translation-dependent mechanism of p53 induction

Abstract

Impaired ribosome biogenesis is attributed to nucleolar disruption and diffusion of a subset of 60S ribosomal proteins, particularly ribosomal protein (rp)L11, into the nucleoplasm, where they inhibit MDM2, leading to p53 induction and cell-cycle arrest1–4. Previously, we demonstrated that deletion of the 40S rpS6 gene in mouse liver prevents hepatocytes from re-entering the cell cycle after partial hepatectomy5. Here, we show that this response leads to an increase in p53, which is recapitulated in culture by rpS6-siRNA treatment and rescued by the simultaneous depletion of p53. However, disruption of biogenesis of 40S ribosomes had no effect on nucleolar integrity, although p53 induction was mediated by rpL11, leading to the finding that the cell selectively upregulates the translation of mRNAs with a polypyrimidine tract at their 5´-transcriptional start site (5´-TOP mRNAs), including that encoding rpL11, on impairment of 40S ribosome biogenesis. Increased 5´-TOP mRNA translation takes place despite continued 60S ribosome biogenesis and a decrease in global translation. Thus, in proliferative human disorders involving hypomorphic mutations in 40S ribosomal proteins6,7, specific targeting of rpL11 upregulation would spare other stress pathways that mediate the potential benefits of p53 induction8.

The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway

“…5G). Similar defects in the 60S/40S ratio have been reported upon knockdown of large ribosome subunit proteins RPL7a, RPL11, RPL5, RPL14, RPL26, RPL35a 48,49,50 . The combination of the data, suggest that the activation of p53 by MLN4924 is not due to RNA Pol I inhibition but rather due to reorganisation of the nucleolar proteome that involves targeting RPs.…”

Hematopoietic defects in rps29 mutant zebrafish depend upon p53 activation

“…GSEA shows strong enrichment for a p53 activation gene signature, as 22 out of 31 genes in a p53-dependent irradiation signature are also up in the rps29 mutant. Studies from others suggest that the mechanism of p53 activation is nucleolar/ribosomal stress[13]. In this model, a mutated ribosomal protein prevents ribosomal subunit formation, leading to an increase in free ribosomal proteins.…”

“…p53 inactivation also rescues craniofacial abnormalities in mouse models of Treacher Collins Syndrome, where mutations affect ribosome biogenesis[12]. In a mouse model of conditional rps6 knockdown, p53 is activated[13]. Mechanistic studies in this system suggest that levels of some free ribosomal proteins are increased as a result of impaired ribosome biogenesis.…”

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

“…As rpL11 increases in the translational level in response to nucleolar/ribosomal stress, we suppose that the early activated c-myc will transduce the signal to the expression of L11 (Fumagalli et al, 2009). Subsequently, increased rpL11 will be also involved in the p53 activation and negatively regulate the level of c-myc.…”

“…Furthermore, it was shown that conditional knockout of rpS6 in the thymus causes failure of T-cell development (Sulic et al, 2005) because of the activation of a p53-dependent checkpoint rather than a defect in protein translation. Another report showed that the activation of p53 by rpS6 depletion resulted in the construction of a rpL11-Mdm2-p53 circuit dependent upon 5 0 -TOP mRNA translation (Fumagalli et al, 2009).…”