A translational control mechanism in p53-dependent apoptosis

A translational control mechanism in p53-dependent apoptosis

There is an ongoing battle between cancer cells and p53, the protein known as 'the guardian of the genome', and a study conducted identified a number of factors that influence the outcome of this battle and therefore the effectiveness of cancer treatments.

Scientists did not know, so far, which elements could lead to two opposite scenarios, of which one is more desirable in therapeutic terms: in one scenario, cancer cells stop proliferating, in the other their death rate increases. Both these outcomes are regulated by the guardian of the genome, the protein p53. Based on the new findings, a specific factor, a protein known as DHX30, determines the way in which p53 can lead cancer cells to their death.

Authors report a translational control mechanism shaping p53-dependent apoptosis. Using polysome profiling, they establish a small molecule activator of p53, Nutlin, induced apoptosis to associate with the enhanced translation of mRNAs carrying multiple copies of an identified 3′ UTR CG-rich motif mediating p53-dependent death (CGPD-motif).

Scientists identify PCBP2 and DHX30 as CGPD-motif interactors. They find that in cells undergoing persistent cell cycle arrest in response to Nutlin, CGPD-motif mRNAs are repressed by the PCBP2-dependent binding of DHX30 to the motif. Upon DHX30 depletion in these cells, the translation of CGPD-motif mRNAs increases, and the response to Nutlin shifts toward apoptosis. Instead, DHX30 inducible overexpression leads to decreased translation of CGPD-motif mRNAs.

A member of the research team, explained: "When cancer cells are treated with a certain drug, it is the action of this switch (DHX30) that makes them to go towards cell death and not in the direction of cell cycle arrest". Another team leader added: "The drug activates p53, the well-known guardian of the genome, which oversees the various pathways of cancer cells. Scientists have thought for decades that we could make cancer cells take the direction of programmed cell death by intervening 'upstream' of p53". The first author of the study, clarified: "What we argue, instead, is that a significant part of that decision is made 'downstream' of p53. In other words, the activation of p53 in cancer cells can lead to a number of possible responses in the cells; the 'switch' that we identified regulates the response that could be the most important for therapeutic reasons. When there is no interaction between DHX30 and relevant mRNAs, cancer cells die".

This is an important discovery to develop more tailored and effective molecular treatments, especially to treat some types of tumors, for example solid tumors in the colon, breast, lung.