The protective effect of arrest

That the apoptotic function of p53 protects cells from tumorigenesis has long been known, but what part does cell-cycle arrest have in the tumour- suppressive arsenal of p53? Guillermina Lozano and colleagues report in the January issue of Nature Genetics that the checkpoint function of p53 might be important for preserving genomic stability and so for suppressing tumorigenesis.

A TP53 point mutation has been found in human tumours that results in a protein that is unable to induce apoptosis, but is still able to induce arrest. The authors generated mice that were homozygous for an equivalent mutation: a guanine to cytosine mutation in base 515 of Trp53 — Trp53^515C/515C — which corresponds to an arginine to proline amino-acid substitution at residue 172. They isolated mouse embryonic fibroblasts (MEFs) from these mice and treated them with γ-radiation. The Trp53^515C/515C MEFs were better able to arrest than Trp53-null MEFs following γ-radiation, but did not arrest as effectively as wild-type MEFs. The extent of cell-cycle arrest correlated with the ability to induce expression of the cyclin-dependent kinase inhibitor Waf1.

As expected, the Trp53^515C/515C MEFs were resistant to apoptosis that was induced by various conditions — exposure to doxorubicin and serum deprivation. Trp53^515C/515C thymocytes were also resistant to apoptosis that was induced by γ-radiation, but were sensitive to apoptosis that was induced by dexamethasone, which operates through a p53-independent pathway.

So, what effect does this mutation have on the ability of p53 to protect cells from tumorigenesis? Whereas 90% of Trp53-null mice had developed tumours by 7 months, only 15% of Trp53^515C/515C mice had succumbed to tumorigenesis. The Trp53^515C/515C mice eventually developed lymphomas and sarcomas, but these were of a different type to the Trp53-null mice and are thought to have arisen through a different mechanism.

Apoptosis was detected at low levels in tumours from both Trp53-null and Trp53^515C/515C mice, so what could account for the difference in tumour type and latency? Loss of p53 characteristically results in highly aneuploid cells, but this was not found to be the case in the Trp53^515C/515C cells — they tended to be diploid or tetraploid. Genome stability therefore seems to protect against early-onset tumorigenesis. The mechanism by which p53 suppresses aneuploidy is thought to be by controlling centrosome duplication — more than 50% of Trp53-null MEFs frequently contained three or more centrosomes, whereas 85% of Trp53^515C/515C MEFs contained just two.

So, although the ability of p53 to induce apoptosis is important for preventing tumorigenesis, it is not the only mechanism that matters. The prevention of genome instability — possibly by inducing cell-cycle arrest — also has a significant protective effect.