Abstract
Werner syndrome (WS) results from dysfunction of the WRN protein, and is associated with premature aging and early death. Here we report that loss of WRN function elicits accumulation of the Yes-associated protein (YAP protein), a major effector of the Hippo tumor suppressor pathway, both experimentally and in WS-derived fibroblasts. YAP upregulation correlates with slower cell proliferation and accelerated senescence, which are partially mediated by the formation of a complex between YAP and the PML protein, whose activity promotes p53 activation. The ATM kinase is necessary for YAP and PML accumulation in WRN-depleted cells. Notably, the depletion of either YAP or PML partially impairs the induction of senescence following WRN loss. Altogether, our findings reveal that loss of WRN activity triggers the activation of an ATM-YAP-PML-p53 axis, thereby accelerating cellular senescence. The latter has features of SASP (senescence-associated secretory phenotype), whose protumorigenic properties are potentiated by YAP, PML and p53 depletion.
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Abbreviations
- WS:
-
Werner syndrome
- WRN:
-
Werner syndrome protein
- YAP:
-
Yes-associated protein
- PML:
-
Promyelocytic Leukemia protein
- SASP:
-
Senescence-associated secretory phenotype
- SA-β-Gal:
-
Senescence-associated β-galactosidase
- BrdU:
-
5-Bromo-2′-deoxy-uridine
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Acknowledgements
We thank Virginia Mazack for valuable comments on the first version of the manuscript. This work was supported by AIRC (no. 10454 to G B and no. 5954 to SS), by PA Breast Cancer Coalition Grants (no. 60707 and no. 920093) plus the Geisinger Clinic (to MS).
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Fausti, F., Di Agostino, S., Cioce, M. et al. ATM kinase enables the functional axis of YAP, PML and p53 to ameliorate loss of Werner protein-mediated oncogenic senescence. Cell Death Differ 20, 1498–1509 (2013). https://doi.org/10.1038/cdd.2013.101
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DOI: https://doi.org/10.1038/cdd.2013.101
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