Effect of aberrant ribosome biogenesis on wild-type and mutant p53 in cancer cells

The tumor suppressor p53 plays a central role in the protection against DNA damage and other forms of stress, primarily by inducing cell cycle arrest or apoptosis. Missense mutation of p53, which is one of the most frequent genetic alterations detected in human cancers, inactivates these growth regulatory functions; in addition, mutant p53 often acquires tumor-promoting activities (gain-of-function). A complete and thorough understanding of the signaling circuitry that regulates wild-type and mutant p53 functions is therefore a primary objective for basic cancer research, since it may lead to development of important tools for diagnosis and therapy of tumors. One crucial component of such knowledge is the molecular mechanism leading to protein activation. Deregulated ribosome biogenesis is commonly observed in cancers as a result of increased biosynthetic demand due to uncontrolled cell proliferation. Cells actively monitor the fidelity of ribosome biogenesis, activating cellular checkpoints when this process is altered. Indeed, perturbations to many aspects of ribosome biogenesis generate a †œnucleolar stress†� that triggers a p53 response. Evidence in animal models indicates that the ribosomal-p53 checkpoint is indeed important for tumor suppression in vivo. In the recent past, we identified the nucleolar protein GTPBP4 as a novel p53 interactor, and established a functional link between the two proteins by demonstrating that GTPBP4 depletion promotes p53 accumulation and activation. In this Thesis, I demonstrate that GTPBP4 depletion affects 28S rRNA processing, generating a †œnucleolar stress†� responsible for p53 stabilization. The molecular mechanism responsible for such accumulation relies on the binding of ribosomal proteins to Mdm2. In parallel, I report that the same molecular mechanism leading to wild-type p53 stabilization upon ribosomal stress, can also promote mutant p53 accumulation in cancer cells. Thus, deregulated ribosome biogenesis may contribute to the stability of mutant p53 in tumors. These results collectively suggest that upon alterations in ribosome biogenesis, the TP53 status may be critical to drive the nucleolar surveillance pathway towards a tumor suppressive or oncogenic outcome.