Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency

Abstract

The Myc oncogene regulates the expression of multiple components of the protein synthetic machinery, including ribosomal proteins, initiation factors of translation, Pol III, and rDNA1,2. An outstanding question is whether and how increasing the cellular protein synthesis capacity can affect the multi-step process leading to cancer. We utilized ribosomal protein heterozygote mice as a genetic tool to restore increased protein synthesis in Eμ–Myc/+ transgenic mice to normal levels and show that in this context Myc's oncogenic potential is suppressed. Our findings demonstrate that the ability of Myc to increase protein synthesis directly augments cell size and is sufficient to accelerate cell cycle progression independently of known cell cycle targets transcriptionally regulated by Myc. In addition, when protein synthesis is restored to normal levels, Myc overexpressing precancerous cells are more efficiently eliminated by programmed cell death. Our findings reveal a novel paradigm that links increases in general protein synthesis rates downstream of an oncogenic signal to a specific molecular impairment in the modality of translation initiation employed to regulate the expression of selective mRNAs. We show that an aberrant increase in cap-dependent translation downstream Myc hyperactivation specifically impairs the translational switch to internal ribosomal entry site (IRES)-dependent translation required for accurate mitotic progression. Failure of this translational switch results in reduced mitotic-specific expression of the endogenous IRES-dependent form of Cdk11 (p58-PITSLRE)3-5, which leads to cytokinesis defects and is associated with increased centrosome numbers and genome instability in Eμ–Myc/+ mice. When accurate translational control is re-established in Eμ–Myc/+ mice, genome instability is suppressed. Our findings reveal how perturbations in translational control provide a highly specific outcome on gene expression, genome stability, and cancer initiation that have important implications for understanding the molecular mechanism of cancer formation at the post-genomic level.

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

“…However, p53 induction was abolished by knockdown of c-Myc, indicating that c-Myc activity is necessary to stabilize p53 protein. Interestingly, recent studies have shown that ribosomal protein haploinsufficiency suppresses the activity of c-Myc (Barna et al, 2008). In conjunction with our results, this suppression of c-Myc activity may be caused by reduced level of c-Myc.…”

Significance of Polypyrimidine Tract–Binding Protein 1 Expression in Colorectal Cancer

“…However, our data indicate that PTBP1 have a positive effect on CKD11 p58 expression. Moreover, the previous report indicates that MYC might play an important role and positive effect on IRES-dependent translation (54). Further study might reveal this discrepancy.…”

Biological Relevance and Therapeutic Potential of the Hypusine Modification System

“…Furthermore, our studies on glioblastoma cell lines have shown a higher sensitivity of tumor cells against the inhibition of hypusine synthesis compared with normal human astrocytes (16), suggesting that certain malignant cells depend on an activated hypusinedependent translation that is above the activation level in normal cells. An intriguing observation made by using another tumor model is that haploinsufficiency of ribosomal proteins attenuates Myc-dependent malignant transformation without affecting normal cells (72). This clearly highlights the dependence of tumor cells on elevated translational activity.…”