Loss of Peter Pan protein is associated with cell cycle defects and apoptotic events
| Autor: | David P. Dannheisig, Astrid S. Pfister, Maria T. Meyer, Melanie Philipp, Lars D. Maerz, Marina Keil |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Nucleolus Ribosome biogenesis Apoptosis Ataxia Telangiectasia Mutated Proteins Histones 03 medical and health sciences 0302 clinical medicine Humans Molecular Biology Gene knockdown Kinase Cell growth Chemistry Nuclear Proteins Cell Biology Cell cycle HCT116 Cells Cell biology G2 Phase Cell Cycle Checkpoints 030104 developmental biology 030220 oncology & carcinogenesis Cancer cell M Phase Cell Cycle Checkpoints Tumor Suppressor Protein p53 Cell Nucleolus Cytokinesis HeLa Cells Signal Transduction |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1866:882-895 |
| ISSN: | 0167-4889 |
| DOI: | 10.1016/j.bbamcr.2019.01.010 |
| Popis: | The nucleolus is a subnuclear compartment, which governs ribosome biogenesis. Moreover, it functions as hub in the stress response by orchestrating a variety of processes, such as regulation of cell cycle progression, senescence and apoptosis. Emerging evidence links the nucleolus also to the control of genomic stability and the development of human malignancies. Peter Pan (PPAN) is an essential ribosome biogenesis factor localized to nucleoli and mitochondria. We earlier showed that PPAN depletion triggers p53-independent nucleolar stress and apoptosis. In this study we investigated the precise localization of nucleolar PPAN during cell cycle and its function in cell cycle regulation. We show that PPAN knockdown impairs cell proliferation and induces G0/G1 as well as later G2/M cell cycle arrest in cancer cells. Although PPAN knockdown stabilizes the tumor suppressor p53 and induces CDKN1A/p21, the proliferation defects occur largely in a p53/p21-independent manner. We noticed a reduced number of knockdown cells entering cytokinesis and an elevation of binucleation. PPAN knockdown is also associated with increased H2A.X phosphorylation (γH2A.X) in cancer cells. We evaluated a potential signaling axis through the DNA damage response kinases ATM and ATR and alternatively apoptosis as a potent driver of γH2A.X. Interestingly, PPAN knockdown does not involve activation of ATM/ATR. Instead, γH2A.X is generated as a consequence of apoptosis induction in cancer cells. Strikingly, PPAN depletion in human fibroblasts did neither provoke apoptosis nor H2A.X phosphorylation, but recapitulated p53 stabilization. In summary, our data underline the notion that the PPAN-mediated, p53-independent nucleolar stress response has multiple facets. |
| Databáze: | OpenAIRE |
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