A newly identified interaction between the ribosomal protein L11 and a negative regulator of p53, HDM2, can lead to the stabilization and activation of p53 under conditions of altered ribosome biogenesis. This finding, as reported by Karen Vousden and colleagues in Cancer Cell, is thought to represent a new stress-induced pathway for p53 stabilization.

Using an HDM2 fragment as bait, Vousden and co-workers identified L11 in a yeast two-hybrid screen. The interaction between L11 and HDM2 was enhanced in response to actinomycin-D treatment, which inhibits RNA polymerase I and leads to changes in ribosomal biogenesis.

When overexpressed, L11 stabilized both p53 and HDM2. The interaction of L11 with HDM2, which has E3 ligase activity, inhibited the ability of HDM2 to target both p53 and itself for ubiquitylation and degradation. Importantly, L11 expression had no effect on the stability of a p53 mutant that lacked the HDM2-binding site, which indicates that L11's main activity is to inhibit HDM2-mediated p53 degradation. This function is similar to that of a small protein known as ARF, and the authors suggest that there might be other HDM2-binding proteins that regulate p53 activity in response to different stress signals.

ARF-null cells that were transfected with L11 arrested in G1 — the same result that is seen in cells transfected with ARF. To show that this cell-cycle arrest was the result of p53 activation, the authors co-expressed papillomavirus protein E6, which targets p53 for degradation. Indeed, E6-mediated inhibition of p53 caused a decrease in G1 arrest.

The authors suggest that this new mechanism “...might play a role in the response to abnormalities in ribosomal biogenesis induced by abnormal metabolic conditions that could occur during tumor development”. Whether L11 has a role in stabilizing p53 in response to other stress signals remains an open question for now. Other ribosomal proteins that bind HDM2 might function in the same way.