The role of deregulated protein synthesis control in Myc-induced tumorigenesis Deregulation of Myc activity is one of the most frequent oncogenic lesions underlying human cancers. The long-term objective of this proposal is to elucidate the molecular and cellular basis for how Myc-dependent increases in protein synthesis lead to tumor formation. Myc directly increases protein synthesis rates by controlling the expression of multiple components of the protein synthetic machinery, including ribosomal proteins, initiation factors of translation, Pol III and rDNA. The role of Myc-dependent increases in protein synthesis towards the multi-step process leading to cancer remains unknown. We utilized ribosomal protein heterozygote mice as a genetic tool to selectively restore accurate protein synthesis control in E?-Myc/+ mice 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. These findings genetically demonstrate for the first time that an increase in protein synthesis downstream of Myc oncogenic signaling has a direct and causal role in tumorigenesis. We further show that the continuous stimulation of cap-dependent translation downstream of Myc-hyperactivation specifically impairs the translational switch between cap- and internal ribosomal entry site (IRES)-dependent translation required for accurate mitotic progression. This translational switch failure leads to cytokinesis failure and is associated with increased genome instability in E?-Myc/+ mice. All together, these findings strongly suggest that Myc oncogenic signaling may monopolize the translational machinery to elicit cooperative effects on cell growth, cell cycle progression, and genome instability as a mechanism for cancer initiation. These results lay the foundation for the goals of this proposal centered on understanding how Myc-dependent perturbations in translational control provide a highly specific outcome on gene expression, genome stability, and cancer initiation.
In Aim 1 we will define the mechanism(s) by which increased cell growth, as a consequence of augmented protein synthesis, promotes cell division downstream of Myc hyperactivation.
In Aim 2 we will assess the requirement of eIF4E hyperactivation in lymphomagenesis and the mitotic translational failure that underlies genome instability downstream of oncogenic Myc signaling. Finally, in Aim 3 we will define the role of Myc-induced cell competition in cancer development.
Statement of Relevance for Public Health The goal of this proposal is to elucidate the mechanisms by which Myc-dependent increases in protein synthesis lead to tumor formation. Myc is the most frequently deregulated oncogene in human cancers. Our work could help to refine diagnosis and therapy for patients that develop cancer as a consequence of disruptions in protein synthesis control.
|Truitt, Morgan L; Conn, Crystal S; Shi, Zhen et al. (2015) Differential Requirements for eIF4E Dose in Normal Development and Cancer. Cell 162:59-71|
|Pelletier, Jerry; Graff, Jeremy; Ruggero, Davide et al. (2015) Targeting the eIF4F translation initiation complex: a critical nexus for cancer development. Cancer Res 75:250-63|
|Cunningham, John T; Moreno, Melissa V; Lodi, Alessia et al. (2014) Protein and nucleotide biosynthesis are coupled by a single rate-limiting enzyme, PRPS2, to drive cancer. Cell 157:1088-103|
|Barna, Maria; Ruggero, Davide (2014) Tailor made protein synthesis for HSCs. Cell Stem Cell 14:423-4|
|Cunningham, John T; Pourdehnad, Michael; Stumpf, Craig R et al. (2013) Investigating Myc-dependent translational regulation in normal and cancer cells. Methods Mol Biol 1012:201-12|
|Cunningham, John T; Ruggero, Davide (2013) New connections between old pathways: PDK1 signaling promotes cellular transformation through PLK1-dependent MYC stabilization. Cancer Discov 3:1099-102|
|Ruggero, Davide (2013) Translational control in cancer etiology. Cold Spring Harb Perspect Biol 5:|
|Stumpf, Craig R; Moreno, Melissa V; Olshen, Adam B et al. (2013) The translational landscape of the mammalian cell cycle. Mol Cell 52:574-82|
|Olshen, Adam B; Hsieh, Andrew C; Stumpf, Craig R et al. (2013) Assessing gene-level translational control from ribosome profiling. Bioinformatics 29:2995-3002|
|Gkogkas, Christos G; Khoutorsky, Arkady; Ran, Israeli et al. (2013) Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 493:371-7|
Showing the most recent 10 out of 19 publications