Translation Stress Regulates Ribosome Synthesis and Cell Proliferation

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2018 Nov 30

PMID 30486342

Citations 16

Authors

Sivakumar Vadivel Gnanasundram

Robin Fahraeus

Affiliations

Soon will be listed here.

Abstract

Ribosome and protein synthesis are major metabolic events that control cellular growth and proliferation. Impairment in ribosome biogenesis pathways and mRNA translation is associated with pathologies such as cancer and developmental disorders. Processes that control global protein synthesis are tightly regulated at different levels by numerous factors and linked with multiple cellular signaling pathways. Several of these merge on the growth promoting factor c-Myc, which induces ribosome biogenesis by stimulating Pol I, Pol II, and Pol III transcription. However, how cells sense and respond to mRNA translation stress is not well understood. It was more recently shown that mRNA translation stress activates c-Myc, through a specific induction of E2F1 synthesis via a PI3Kδ-dependent pathway. This review focuses on how this novel feedback pathway stimulates cellular growth and proliferation pathways to synchronize protein synthesis with ribosome biogenesis. It also describes for the first time the oncogenic activity of the mRNA, and not the encoded protein.

Citing Articles

Preliminary screening of new biomarkers for sepsis using bioinformatics and experimental validation.

Wang H, Xiong W, Zhong W, Hu Y PLoS One. 2025; 20(1):e0317608.

PMID: 39854580 PMC: 11759385. DOI: 10.1371/journal.pone.0317608.

The Influence of Extra-Ribosomal Functions of Eukaryotic Ribosomal Proteins on Viral Infection.

Zhao Z, Ruan S, Li Y, Qi T, Qi Y, Huang Y Biomolecules. 2025; 14(12.

PMID: 39766272 PMC: 11674327. DOI: 10.3390/biom14121565.

Cross-species single-cell landscapes identify the pathogenic gene characteristics of inherited retinal diseases.

Hu H, Liu F, Gao P, Huang Y, Jia D, Reilly J Front Genet. 2024; 15:1409016.

PMID: 39055259 PMC: 11269129. DOI: 10.3389/fgene.2024.1409016.

Transcriptomic changes behind Sparus aurata hepatic response to different aquaculture challenges: An RNA-seq study and multiomics integration.

de Magalhaes C, Sandoval K, Kagan F, McCormack G, Schrama D, Carrilho R PLoS One. 2024; 19(3):e0300472.

PMID: 38517901 PMC: 10959376. DOI: 10.1371/journal.pone.0300472.

The induction of p53 correlates with defects in the production, but not the levels, of the small ribosomal subunit and stalled large ribosomal subunit biogenesis.

Eastham M, Pelava A, Wells G, Lee J, Lawrence I, Stewart J Nucleic Acids Res. 2023; 51(17):9397-9414.

PMID: 37526268 PMC: 10516649. DOI: 10.1093/nar/gkad637.

References

Sherr C, Roberts J . CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999; 13(12):1501-12. DOI: 10.1101/gad.13.12.1501. View

Harbour J, Luo R, Dei Santi A, Postigo A, Dean D . Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell. 1999; 98(6):859-69. DOI: 10.1016/s0092-8674(00)81519-6. View

Sirri V, Roussel P, Hernandez-Verdun D . The mitotically phosphorylated form of the transcription termination factor TTF-1 is associated with the repressed rDNA transcription machinery. J Cell Sci. 1999; 112 ( Pt 19):3259-68. DOI: 10.1242/jcs.112.19.3259. View

Sirri V, Roussel P, Hernandez-Verdun D . In vivo release of mitotic silencing of ribosomal gene transcription does not give rise to precursor ribosomal RNA processing. J Cell Biol. 2000; 148(2):259-70. PMC: 2174287. DOI: 10.1083/jcb.148.2.259. View

Thomas G . An encore for ribosome biogenesis in the control of cell proliferation. Nat Cell Biol. 2000; 2(5):E71-2. DOI: 10.1038/35010581. View

Volarevic S, Stewart M, Ledermann B, Zilberman F, Terracciano L, Montini E . Proliferation, but not growth, blocked by conditional deletion of 40S ribosomal protein S6. Science. 2000; 288(5473):2045-7. DOI: 10.1126/science.288.5473.2045. View

Hannan K, Hannan R, Smith S, Jefferson L, Lun M, Rothblum L . Rb and p130 regulate RNA polymerase I transcription: Rb disrupts the interaction between UBF and SL-1. Oncogene. 2000; 19(43):4988-99. DOI: 10.1038/sj.onc.1203875. View

Bodem J, Dobreva G, Iben S, Zentgraf H, Delius H, Vingron M . TIF-IA, the factor mediating growth-dependent control of ribosomal RNA synthesis, is the mammalian homolog of yeast Rrn3p. EMBO Rep. 2001; 1(2):171-5. PMC: 1084264. DOI: 10.1093/embo-reports/kvd032. View

Ciarmatori S, Scott P, Sutcliffe J, McLees A, Alzuherri H, Dannenberg J . Overlapping functions of the pRb family in the regulation of rRNA synthesis. Mol Cell Biol. 2001; 21(17):5806-14. PMC: 87300. DOI: 10.1128/MCB.21.17.5806-5814.2001. View

10.

Stefanovsky V, Pelletier G, Hannan R, Gagnon-Kugler T, Rothblum L, Moss T . An immediate response of ribosomal transcription to growth factor stimulation in mammals is mediated by ERK phosphorylation of UBF. Mol Cell. 2001; 8(5):1063-73. DOI: 10.1016/s1097-2765(01)00384-7. View

11.

Tenson T, Ehrenberg M . Regulatory nascent peptides in the ribosomal tunnel. Cell. 2002; 108(5):591-4. DOI: 10.1016/s0092-8674(02)00669-4. View

12.

Koyasu S . The role of PI3K in immune cells. Nat Immunol. 2003; 4(4):313-9. DOI: 10.1038/ni0403-313. View

13.

Sawyer C, Sturge J, Bennett D, OHare M, Allen W, Bain J . Regulation of breast cancer cell chemotaxis by the phosphoinositide 3-kinase p110delta. Cancer Res. 2003; 63(7):1667-75. View

14.

Felton-Edkins Z, Kenneth N, Brown T, Daly N, Gomez-Roman N, Grandori C . Direct regulation of RNA polymerase III transcription by RB, p53 and c-Myc. Cell Cycle. 2003; 2(3):181-4. View

15.

Tschochner H, Hurt E . Pre-ribosomes on the road from the nucleolus to the cytoplasm. Trends Cell Biol. 2003; 13(5):255-63. DOI: 10.1016/s0962-8924(03)00054-0. View

16.

Grummt I . Life on a planet of its own: regulation of RNA polymerase I transcription in the nucleolus. Genes Dev. 2003; 17(14):1691-702. DOI: 10.1101/gad.1098503R. View

17.

Yin Y, Manoury B, Fahraeus R . Self-inhibition of synthesis and antigen presentation by Epstein-Barr virus-encoded EBNA1. Science. 2003; 301(5638):1371-4. DOI: 10.1126/science.1088902. View

18.

SHWACHMAN H, DIAMOND L, Oski F, Khaw K . THE SYNDROME OF PANCREATIC INSUFFICIENCY AND BONE MARROW DYSFUNCTION. J Pediatr. 1964; 65:645-63. DOI: 10.1016/s0022-3476(64)80150-5. View

19.

Hannan K, Brandenburger Y, Jenkins A, Sharkey K, Cavanaugh A, Rothblum L . mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF. Mol Cell Biol. 2003; 23(23):8862-77. PMC: 262650. DOI: 10.1128/MCB.23.23.8862-8877.2003. View

20.

Mayer C, Zhao J, Yuan X, Grummt I . mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability. Genes Dev. 2004; 18(4):423-34. PMC: 359396. DOI: 10.1101/gad.285504. View