Abstract
TPL2-NPM-p53 pathway monitors nucleolar stress.
Highlights
It has long been appreciated that upon exposure of cells to distinct genotoxic agents that perturb nucleolar structure and ribosome biogenesis, the nucleolar proteins nucleophosmin (NPM) and alternative reading frame (ARF) tumor suppressor are engaged to activate p53
Upon genotoxic stress this NPM pool becomes de-phosphorylated by activated PP1β [5], stabilizes and translocates to the nucleoplasm where it sequesters HDM2 away from p53 leading to a robust p53 response (Figure 1)
A number of outstanding questions remain unanswered. How do these distinct Tumor Progression Locus 2 (TPL2) functions intertwine to achieve control of processes relevant to tumorigenesis such as cell cycle arrest, apoptosis and senescence? What is the relationship between nucleolar TPL2 and oncogene-induced ARF or the RPL5/RPL11/5S rRNA/HDM2/p53 signaling pathway? Do these pathways sense distinct stress-induced nucleolar lesions and do they synergize in p53 activation and tumor suppression?
Summary
It has long been appreciated that upon exposure of cells to distinct genotoxic agents that perturb nucleolar structure and ribosome biogenesis, the nucleolar proteins nucleophosmin (NPM) and alternative reading frame (ARF) tumor suppressor are engaged to activate p53. A recent study by Kanellis et al [3] provides novel insight into the intricate management of p53 activation upon “nucleolar stress” by identifying Tumor Progression Locus 2 (TPL2; known as COT and MAP3K8) as a physical and functional partner of NPM.
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