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

Carmen Morcelle,Antonio Gentilella,Sandra Menoyo,Albert Tauler,Francisco D Morón-Duran,Sara C Kozma,George Thomas

doi:10.1158/0008-5472.can-18-2718

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.

Highlights

In a proliferating cell, the proto-oncogene MYC drives genomewide transcription, of those genes involved in cellcycle progression (1, 2)
Analysis of an agarose gel loaded with equal amounts of total cellular rRNA, as detected by ethidium bromide (EB) staining (Fig. 1C, left), shows that MYC depletion had a profound effect on the rate of incorporation of 3H-uridine into the newly synthesized 18S and 28S rRNA, when compared with siNStreated cells (Fig. 1C, right)
We show that the impaired ribosome biogenesis checkpoint (IRBC) complex, which is activated in response to impaired ribosome biogenesis (2), controls p53 protein levels in response to MYC

Summary

Introduction

The proto-oncogene MYC drives genomewide transcription, of those genes involved in cellcycle progression (1, 2). Among the chief functions fulfilled by MYC in cell-cycle progression is the coordinate production of the molecular components that generate nascent ribosomes, needed for increased protein synthetic capacity in a rapidly growing cell (2). This observation has led to the finding that oncogenic MYC-driven tumors are addicted to the hyperactivation of ribosome biogenesis (3), which may serve as an Achilles' heel for the treatment of such tumors (4). Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

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