The Wnt Target Protein Peter Pan Defines a Novel p53-independent Nucleolar Stress-Response Pathway

Abstract

Proper ribosome formation is a prerequisite for cell growth and proliferation. Failure of this process results in nucleolar stress and p53-mediated apoptosis. The Wnt target Peter Pan (PPAN) is required for 45 S rRNA maturation. So far, the role of PPAN in nucleolar stress response has remained elusive. We demonstrate that PPAN localizes to mitochondria in addition to its nucleolar localization and inhibits the mitochondrial apoptosis pathway in a p53-independent manner. Loss of PPAN induces BAX stabilization, depolarization of mitochondria, and release of cytochrome c, demonstrating its important role as an anti-apoptotic factor. Staurosporine-induced nucleolar stress and apoptosis disrupt nucleolar PPAN localization and induce its accumulation in the cytoplasm. This is accompanied by phosphorylation and subsequent cleavage of PPAN by caspases. Moreover, we show that PPAN is a novel interaction partner of the anti-apoptotic protein nucleophosmin (NPM). PPAN depletion induces NPM and upstream-binding factor (UBF) degradation, which is independent of caspases. In summary, we provide evidence for a novel nucleolar stress-response pathway involving PPAN, NPM, and BAX to guarantee cell survival in a p53-independent manner.

Keywords: Apoptosis; Bax; Mitochondria; Nucleoli; Nucleophosmin; Peter Pan; Ribosome Biogenesis; Staurosporine; Stress; Wnt Signaling.