Cell-based studies showed that several Mdm2-binding ribosomal proteins, upon overexpression, stabilize and activate p53. In contrast, here we show in a mouse knockout study that Mdm2-binding ribosomal protein S27-like (Rps27l), upon disruption, activates p53. Germline inactivation of Rps27l triggers ribosomal stress to stabilize Mdm2, which degrades Mdm4 to reduce Mdm2-Mdm4 E3 ligase towards p53, leading to p53-dependent apoptotic depletion of hematopoietic stem cells and postnatal death, which is rescued by Trp53 deletion. Paradoxically, while increased p53 is expected to inhibit tumorigenesis, Rps27l−/−;Trp53+/− mice develop lymphomas at higher incidence with p53 loss-of-heterozygosity and severe genome aneuploidy, suggesting that Rps27l disruption impose a selection pressure against p53. Thus, Rps27l has dual functions in p53 regulation: under Trp53+/+ background, Rps27l disruption triggers ribosomal stress to induce p53 and apoptosis, whereas under Trp53+/− background, Rps27l disruption triggers genomic instability and Trp53 deletion to promote tumorigenesis. Our study provides a new paradigm of p53 regulation.
There are over a hundred different types of cancer that can affect humans; but, in general, all cancers are caused by mutations that cause cells to grow and divide abnormally. ‘Tumor suppressor genes’ are genes that normally protect a cell from genetic changes that can lead a cell towards becoming cancerous.
About half of all cancers in humans have a mutation in one of the two copies of a tumor suppressor gene that encodes a protein called p53, which helps to control how and when cells grow and divide. In normal cells, the p53 protein can be activated in various ways. Damage to a cell's DNA triggers p53 to stop the cell growing, which gives the cell time to repair the DNA damage. However, if the damage is too severe and cannot be repaired, p53 essentially causes the cell to kill itself, via a process called apoptosis. Furthermore, if a cell has problems building new copies of its protein-making machinery, some of the parts (called ribosomal proteins) that make up these molecular machines can also lead to p53 being activated.
By deleting the gene for a protein called Rps27l that is a newly characterized ribosomal protein, Xiong et al. have discovered that, in mice, Rps27I regulates the p53 protein in two different ways. In normal cells, Rps27l appears to inhibit p53, which is likely to encourage cancer to develop. But, if a cell has already lost a copy of the p53 gene—a situation that would normally encourage the cells to accrue further mutations and become cancerous—Rps27l acts as a tumor suppressor. In these mutated cells, the Rps27l protein helps to maintain the stability of the genome and prevent the loss of the second copy of gene for p53, and so protects the cell from becoming cancerous.
Thus Rps27l can either activate or inactivate p53 activity depending on how many copies of the gene for p53 remain intact. The next challenge is to investigate if Rps27l levels determine the early-onset of tumor development in cancer-prone cells seen in patients with Li-Fraumeni syndrome, who are born with a mutated copy of the p53 gene.