Research Paper Volume 16, Issue 5 pp 4116—4137
PR55α-controlled protein phosphatase 2A inhibits p16 expression and blocks cellular senescence induction by γ-irradiation
- 1 Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE 68198, USA
- 2 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
- 3 Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
- 4 Department of Internal Medicine - Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68198, USA
- 5 Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
Received: October 24, 2023 Accepted: February 7, 2024 Published: March 4, 2024
https://doi.org/10.18632/aging.205619How to Cite
Copyright: © 2024 Palanivel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Cellular senescence is a permanent cell cycle arrest that can be triggered by both internal and external genotoxic stressors, such as telomere dysfunction and DNA damage. The execution of senescence is mainly by two pathways, p16/RB and p53/p21, which lead to CDK4/6 inhibition and RB activation to block cell cycle progression. While the regulation of p53/p21 signaling in response to DNA damage and other insults is well-defined, the regulation of the p16/RB pathway in response to various stressors remains poorly understood. Here, we report a novel function of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase, as a potent inhibitor of p16 expression and senescence induction by ionizing radiation (IR), such as γ-rays. The results show that ectopic PR55α expression in normal pancreatic cells inhibits p16 transcription, increases RB phosphorylation, and blocks IR-induced senescence. Conversely, PR55α-knockdown by shRNA in pancreatic cancer cells elevates p16 transcription, reduces RB phosphorylation, and triggers senescence induction after IR. Furthermore, this PR55α function in the regulation of p16 and senescence is p53-independent because it was unaffected by the mutational status of p53. Moreover, PR55α only affects p16 expression but not p14 (ARF) expression, which is also transcribed from the same CDKN2A locus but from an alternative promoter. In normal human tissues, levels of p16 and PR55α proteins were inversely correlated and mutually exclusive. Collectively, these results describe a novel function of PR55α/PP2A in blocking p16/RB signaling and IR-induced cellular senescence.