A large-scale insertional mutagenesis screen in zebrafish has revealed the ability of ribosomal proteins to contribute to tumorigenesis.

Nancy Hopkins and colleagues have generated approximately 500 lines of zebrafish that are heterozygous for a recessive lethal mutation. As many tumour-suppressor genes cause recessive lethality, they searched for lines of fish with obvious tumours or short survival times, and identified 12 tumour-prone lines. These zebrafish mostly developed malignant peripheral-nerve-sheath tumours (81%), as well as some other tumour types.

One line carried a heterozygous mutation in a zebrafish paralogue of the human and mouse tumour-suppressor gene neurofibromatosis 2 (NF2) — so establishing the validity of this approach for identifying cancer genes. Surprisingly, all the other lines carried a heterozygous mutation in genes encoding different ribosomal proteins. All of these mutations reduced or eliminated expression of the genes, indicating that ribosomal proteins do not function as activated oncogene products. Loss of heterozygosity was not observed, so the authors conclude that a simple reduction in the amount of ribosomal protein is sufficient to lead to tumour formation.

How does loss of ribosomal proteins contribute to tumorigenesis? In each line, the authors observed a decrease in the overall amount of ribosomal RNA produced — primarily in the ribosomal subunit with which the mutant gene product was associated. A reduction in the level of protein synthesis could reduce the levels of a critical tumour suppressor, or signal the cell to produce more of the components required for ribosome biogenesis, leading to cell proliferation. Alternatively, a reduction in the number of ribosomes might alter the specificity of mRNAs recruited to the ribosome, changing the translation rate of mRNAs that encode proteins that promote proliferation. These proteins might also have undiscovered functions outside of their role at the ribosome, although it seems unlikely that there could be an important yet unknown function of so many ribosomal proteins.

It is only the loss of specific ribosomal proteins that causes cancer — loss of others had no effect. Hopkins and colleagues haven't identified any particular characteristic of those that were associated with cancer — the cancer-causing gene products could belong to either the small or large ribosomal subunit.

Further studies are needed to determine the reason that this screen resulted in such a high percentage of malignant peripheral-nerve-sheath tumours, and why it led to disruption of ribosomal protein genes in particular. But it offers some interesting new genes to investigate in human tumours which might also have alterations in ribosomal protein function.