Oncogenic MYC Induces the Impaired Ribosome Biogenesis Checkpoint and Stabilizes p53 Independent of Increased Ribosome Content

Abstract

The role of MYC in regulating p53 stability as a function of increased ribosome biogenesis is controversial. On the one hand, it was suggested that MYC drives the overexpression of ribosomal proteins (RP)L5 and RPL11, which bind and inhibit HDM2, stabilizing p53. On the other, it has been proposed that increased ribosome biogenesis leads the consumption of RPL5/RPL11 into nascent ribosomes, reducing p53 levels and enhancing tumorigenesis. Here, we show that the components that make up the recently described impaired ribosome biogenesis checkpoint (IRBC) complex, RPL5, RPL11, and 5S rRNA, are reduced following MYC silencing. This leads to a rapid reduction in p53 protein half-life in an HDM2-dependent manner. In contrast, MYC induction leads to increased ribosome biogenesis and p53 protein stabilization. Unexpectedly, there is no change in free RPL5/RPL11 levels, but there is a striking increase in IRBC complex bound to HDM2. Our data support a cell-intrinsic tumor-suppressor response to MYC expression, which is presently being exploited to treat cancer. Significance: Oncogenic MYC induces the impaired ribosome biogenesis checkpoint, which could be potentially targeted for cancer treatment.

Myc as a Regulator of Ribosome Biogenesis and Cell Competition: A Link to Cancer

“…In DBA it was shown that nucleolar stress due to mutations in RPL5 and RPL11 results in their binding and inhibition of MDM2, which subsequently causes in p53 accumulation [140]. Recently, Myc was shown to stabilize the RPL5-RPL11-5S rRNA complex suggesting it has a role in the control of p53 activation [141]. However, we can speculate that the RPL5-L11 and MDM2-p53 axis may be induced by Myc as the result of a feedback loop required to prevent Myc-induced tumorigenesis.…”

Nucleotide depletion reveals the impaired ribosome biogenesis checkpoint as a barrier against DNA damage

“…Given the dependency of such tumors on ribosome biogenesis (Barna et al , ; van Riggelen et al , ), a search for novel agents that specifically target this process has been initiated (Bywater et al , ; Pelletier et al , ). Importantly, insults to ribosome biogenesis, including c‐Myc‐induced oncogenic stress (Macias et al , ; Morcelle et al , ), also trigger a p53‐mediated cell‐cycle checkpoint, recently termed the impaired ribosome biogenesis checkpoint (IRBC) (Gentilella et al , ; Pelletier et al , ). The IRBC is mediated by a nascent pre‐ribosomal complex containing RPL5 (or uL18), RPL11 (or uL5), and 5S rRNA, which upon insults to ribosome biogenesis, is redirected from its assembly into 60S ribosomes to the binding and inhibition of the p53‐E3‐ubiquitin ligase HDM2 (or MDM2) (Donati et al , ), leading to p53 stabilization (Kubbutat et al , ; Pelletier et al , ).…”

Targeting Protein Synthesis in Colorectal Cancer

“…Consistent with this, a computational study of the MYC expression network from the Cancer Genome Atlas (TCGA) showed that high MYC expression in colon and rectum adenocarcinoma positively correlates with pathways associated with translation, ribosomes, and rRNA [64]. Regarding ribosome biogenesis, enhanced rRNA synthesis in CRC cells is driven by MYC, as MYC depletion reduces nascent levels of 5S, 5.8S, 18S, and 28S rRNAs, which is connected with decreased translation rates [65]. More specifically, there is compelling evidence that rRNA synthesis is hyperactivated in CRC due to APC deficiency in general.…”