Key Points
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Ribosome biogenesis and translation are regulated at multiple levels and are associated with accurate cell growth and proliferation. The loss of key checkpoints during protein synthesis might contribute to the initiation and progression of cancer.
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During specific phases of the cell cycle, the synthesis of rRNA, as well as components of the protein synthesis machinery, is initiated by the phosphorylation of key transcription factors that regulate polymerase I (Pol I) and Pol III activity, respectively. This tight link between cell-cycle progression and protein synthesis exists to ensure accurate cell growth and proliferation, which might be lost in cancer cells.
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p53 and retinoblastoma (RB) repress Pol I and Pol III transcription. In cancer cells, which harbour inactivating mutations in these tumour suppressors, deregulation of Pol I and Pol III activity might contribute to tumorigenesis.
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Several ribosomal proteins are overexpressed in a variety of tumours. It remains to be determined whether this represents a cause or consequence of tumour formation. Increased phosphorylation of the S6 ribosomal protein is thought to result in enhanced translation of specific mRNAs. This raises the possibility that deregulation of ribosomal proteins in tumours might affect the translation of specific target mRNAs.
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MYC and PTEN act as master regulators of ribosome biogenesis and translation control. Their deregulation in tumour cells increases the expression and activity of components of the translation apparatus. It remains to be determined which of the downstream targets of MYC and PTEN involved in controlling protein synthesis are directly responsible for tumour susceptibility.
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Further investigation will be needed to clarify to what extent deregulation in total or specific translation of mRNAs contributes to tumorigenesis. Although mutations in genes that are directly responsible for ribosome biogenesis, such as those encoding the ribosomal protein S19 and DKC1 (the enzyme that modifies rRNA), have been found in cancer susceptibility syndromes, the molecular mechanisms by which these proteins cause cancer remain largely unknown.
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Components of the translation machinery that are overexpressed or deregulated in cancer cells could represent targets for cancer therapy. The macrolide rapamycin, which affects the translation machinery, has already been used in clinical trials as a tumour inhibitory agent.
Abstract
Ribosome biogenesis and translation control are essential cellular processes that are governed at numerous levels. Several tumour suppressors and proto-oncogenes have been found either to affect the formation of the mature ribosome or to regulate the activity of proteins known as translation factors. Disruption in one or more of the steps that control protein biosynthesis has been associated with alterations in the cell cycle and regulation of cell growth. Therefore, certain tumour suppressors and proto-oncogenes might regulate malignant progression by altering the protein synthesis machinery. Although many studies have correlated deregulation of protein biosynthesis with cancer, it remains to be established whether this translates directly into an increase in cancer susceptibility, and under what circumstances.
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Acknowledgements
We are indebted to M. Barna for input, discussion and critical reading of the review. We apologize to the many scientists whose work we did not cite due to space constraints. This work is supported by the National Cancer Institute, the Mouse Model of Human Cancer Consortium (MMHCC) and the Leukemia Lymphoma Society (LLS).
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Glossary
- NUCLEOLUS
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The nucleolus is a suborganelle of the nucleus where rRNA is transcribed, processed and assembled into ribosomal subumits. Ribosomal proteins are added to rRNAs within the nucleolus.
- CRYO-ELECTRON MICROSCOPY
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A technique that is used to study the three-dimensional structures of biomolecules. A sample is rapidly frozen in liquid helium to preserve its structure and then examined in the frozen, hydrated state in a cryoelectron microscope.
- RAPAMYCIN
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Rapamycin is a macrolide with immunosuppressant properties and tumour-inhibitory effects. To exert its effect, rapamycin binds an immunophilin FK-506-binding protein 12, and this complex inhibits the cellular target of rapamycin, mTOR.
- SERIAL ANALYSIS OF GENE EXPRESSION
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(SAGE). A technique that is used to identify and quantitate genes that are differentially expressed between two different samples. Sage libraries are generated by adding a short nucleotide sequence tag (10 base pairs) to cDNAs from different RNA samples that are being analysed. The abundance of a given tag within the SAGE library corresponds to the expression level of the corresponding gene, which can easily be identified by sequencing directly from the transcript tag.
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Ruggero, D., Pandolfi, P. Does the ribosome translate cancer?. Nat Rev Cancer 3, 179–192 (2003). https://doi.org/10.1038/nrc1015
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DOI: https://doi.org/10.1038/nrc1015
