Abstract
The tumor suppressor ARF is transcribed from the INK4a/ARF locus in partly overlapping reading frames with the CDK inhibitor p16Ink4a. ARF is able to antagonize the MDM2-mediated ubiquitination and degradation of p53, leading to either cell cycle arrest or apoptosis, depending on the cellular context. However, recent data point to additional p53-independent functions of mouse p19ARF. Little is known about the dependency of human p14ARF function on p53 and its downstream genes. Therefore, we analysed the mechanism of p14ARF-induced cell cycle arrest in several human cell types. Wild-type HCT116 colon carcinoma cells (p53+/+p21CIP1+/+ 14-3-3σ+/+), but not p53−/− counterparts, underwent G1 and G2 cell cycle arrest following infection with a p14ARF-adenovirus. In p21CIP1−/− cells, p14ARF did not induce G1 or G2 arrest, while 14-3-3σ−/− counterparts were mainly arrested in G1, pointing to essential roles of p21CIP1 in G1 and G2 arrest and cooperative roles of p21 and 14-3-3σ in ARF-mediated G2 arrest. Our data demonstrate a strict p53 and p21CIP1 dependency of p14ARF-induced cell cycle arrest in human cells.
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Acknowledgements
We thank Bert Vogelstein and Heiko Hermeking for cell lines and reagents; Denise Galloway and Jennifer Benanti for LXSN vectors; Karen Vousden for suggestions and discussion; Frank McCormick, Heiko Hermeking, Susanna Trapp, Andreas Baur, Berlinda Verdoodt, Tino Blazek, and Alexander Steinkasserer for comments; and Gerold Schuler for continuing support and encouragement. This work was supported by grants from the ELAN program of the University of Erlangen-Nuremberg and the Deutsche Forschungsgemeinschaft to JO Funk.
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Weber, H., Samuel, T., Rauch, P. et al. Human p14ARF-mediated cell cycle arrest strictly depends on intact p53 signaling pathways. Oncogene 21, 3207–3212 (2002). https://doi.org/10.1038/sj.onc.1205429
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DOI: https://doi.org/10.1038/sj.onc.1205429
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