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Mitogen-activated protein kinase p38 defines the common senescence-signalling pathway
Hiroaki Iwasa1, Jiahuai Han, Fuyuki Ishikawa
1Laboratory of Molecular and Cellular Assembly, Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226-8501, Japan.
Background:
Cellular senescence is a state of irreversible growth arrest shown by normal cells, and has been most extensively studied in replicative senescence caused by telomere shortening. Several conditions, including oncogenic Ras over-expression and inappropriate culture conditions, also induce senescence without telomere shortening. However, it remains unclear how a common set of senescence phenotypes is indistinguishably induced in various types of senescence.
Results:
We demonstrate that p38 mitogen-activated protein kinase (MAPK) plays important causative roles in senescent cells following telomere shortening, Ras-Raf activation, oxidative stress or inappropriate culture conditions. By monitoring the kinetics of p38 activation, we suggest that p38 is activated not directly by the initial stimuli, but in response to unidentified cellular conditions caused by these stimuli. Importantly, this p38-activating condition appears to be defined quantitatively as a sum of continuous and low-level stresses, and remains even after the initial stimuli are withdrawn, which may explain the well-known irreversible nature of cellular senescence. We also show that papilloma virus E7 abolishes the p38-induced growth arrest but not other senescence-associated phenotypes, indicating the differential role of pRb in the downstream of p38.
Conclusion:
These results indicate that p38 comprises the senescence-executing pathway in response to diverse stimuli.
Insights
p38 mitogen-activated protein kinase (MAPK) acts as a central pathway executing cellular senescence. This pathway is activated by various stressors, explaining the irreversible nature of senescence.
Area of Science:
- Cellular and Molecular Biology
- Biochemistry
- Genetics
Background:
- Cellular senescence is irreversible growth arrest.
- Replicative senescence is linked to telomere shortening.
- Other factors like oncogenic Ras and culture conditions also induce senescence.
Purpose of the Study:
- To investigate the common mechanisms underlying diverse senescence induction.
- To identify key signaling pathways involved in cellular senescence.
Main Methods:
- Monitoring p38 mitogen-activated protein kinase (MAPK) activation kinetics.
- Studying senescence phenotypes under various stress conditions.
- Analyzing the role of papilloma virus E7 and pRb.
Main Results:
- p38 MAPK is crucial in senescence induced by telomere shortening, Ras-Raf activation, oxidative stress, and inappropriate culture.
- p38 activation is a response to cumulative stress, not initial stimuli, explaining senescence irreversibility.
- Papilloma virus E7 inhibits p38-induced growth arrest but not other senescence phenotypes.
Conclusions:
- p38 MAPK acts as a common senescence-executing pathway.
- The p38 pathway integrates diverse stress signals to induce irreversible growth arrest.