Human rpL3 induces mitochondrial apoptosis in Calu-6 cells through activation of p21 expression.

It has recently reported that some ribosomal proteins may regulate the cell cycle and apoptosis in response to nucleolar stress through extraribosomal functions. Defects of ribosome assembly promote the binding of some ribosomal proteins to MDM2, activating p53 and p21 to induce cell cycle arrest or apoptosis, depending on the cellular context. Several proteins involved in ribosome assembly, such as Nucleophosmin (NPM), have been proposed as positive regulators of p53-independent p21 expression. We have previously reported that NPM binds to rpL3 in the context of rpL3 expression autoregulatory circuit. We wondered whether this interaction could occur also in the regulation of p21 expression. To verify this hypothesis, we first analyzed changes in p21 protein levels in p53-null Calu-6 cells upon rpL3 overexpression. We observed that the enforced expression of the rpL3 protein resulted in an increase of p21 protein levels. Interestingly, we detected that the rpL3-mediated p21 upregulation activates mitochondrial apoptosis in Calu-6 cells, abrogated by p21 silencing. These data indicate that the mitochondrial apoptosis activated by rpL3 overexpression could be p21-dependent.