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

The role of MYC in regulating p53 stability as a function of increased ribosome biogenesis is controversial. On 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 supports a cell intrinsic tumor suppressor response to MYC expression, which is presently being exploited to treat cancer.