Does the ribosome translate cancer?

Abstract

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. 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. 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. 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. 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. 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. 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.