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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
p18(Hamlet) mediates different p53-dependent responses to DNA-damage inducing agents
Vanesa Lafarga1, Ana Cuadrado, Angel R Nebreda
1CNIO (Spanish National Cancer Center), Madrid, Spain.
Cell Cycle (Georgetown, Tex.)
|August 19, 2007
Summary
The protein p18(Hamlet) (ZNHIT1) mediates cellular stress responses. It enhances p53 (TP53) activity, promoting apoptosis or cell cycle arrest following DNA damage from genotoxic stresses.
Area of Science:
- Cellular Biology
- Molecular Biology
- Stress Response Signaling
Background:
- Cells activate signaling networks to respond to environmental cues and stress.
- p38alpha (MAPK14) kinase and p53 (TP53) transcription factor are key regulators of cellular stress responses.
- Cellular outcomes to stress include cell cycle arrest or apoptosis, mediated by protein phosphorylation and gene activation.
Purpose of the Study:
- To investigate the role of p18(Hamlet) (ZNHIT1) in mediating cellular responses to genotoxic stress.
- To elucidate the mechanism by which p18(Hamlet) influences p53 (TP53)-dependent signaling pathways.
- To characterize p18(Hamlet)'s function in both apoptosis induction and cell cycle arrest.
Main Methods:
- Characterization of p18(Hamlet) as a novel p38alpha (MAPK14) substrate.
- Analysis of p18(Hamlet) protein stabilization upon exposure to genotoxic agents like cisplatin and UV light.
- Assessment of p18(Hamlet)'s effect on p53 (TP53) binding to target gene promoters and subsequent gene expression (e.g., NOXA, PUMA, CDKN1A).
Main Results:
- p18(Hamlet) (ZNHIT1) stabilizes upon genotoxic stress, enhancing p53 (TP53)-mediated activation of pro-apoptotic genes (NOXA, PUMA).
- p18(Hamlet) also mediates p53 (TP53)-dependent cell cycle arrest in response to gamma-irradiation.
- p18(Hamlet) participates in the upregulation of the cell cycle inhibitor p21(Cip1) (CDKN1A).
Conclusions:
- p18(Hamlet) (ZNHIT1) is a crucial mediator of p53 (TP53)-dependent cellular responses to diverse genotoxic stresses.
- This protein plays a significant role in coordinating both apoptosis and cell cycle arrest.
- p18(Hamlet) represents a key node in stress signaling pathways involving p38alpha (MAPK14) and p53 (TP53).
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