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PLK1 targets NOTCH1 during DNA damage and mitotic progression
Carlo De Blasio1, Azzurra Zonfrilli1,2, Matteo Franchitto1
1Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy.
The Journal of Biological Chemistry
|October 11, 2019
Summary
Polo-like kinase 1 (PLK1) regulates NOTCH1 during the cell cycle and DNA damage response. PLK1 inhibition during genotoxic stress maintains NOTCH1, impacting cancer cell signaling.
Area of Science:
- Cell Biology
- Molecular Oncology
- Cancer Signaling Pathways
Background:
- Notch signaling has a dual role in cancer, acting as both a tumor suppressor and oncogene.
- Identifying regulators of NOTCH1's complex function is crucial for understanding carcinogenesis.
Purpose of the Study:
- To investigate the interplay between Polo-like kinase 1 (PLK1) and NOTCH1 during the G2 cell cycle phase and in response to DNA damage.
- To elucidate the role of PLK1 in modulating NOTCH1 activity in cancer cells under genotoxic stress.
Main Methods:
- Chemical library screening targeting kinases to identify regulators of NOTCH1.
- Investigating the PLK1-NOTCH1 interaction in G2 phase cells and during DNA damage response.
- Analyzing PLK1-dependent signaling in response to arsenite-induced genotoxic stress.
Main Results:
- PLK1 regulates NOTCH1 expression during the G2/M transition.
- During DNA damage, PLK1 is inhibited, but NOTCH1 expression is maintained, indicating a functional interaction.
- Arsenite-induced stress triggers a PLK1-dependent response that antagonizes NOTCH1's role in the DNA damage checkpoint.
Conclusions:
- Notch signaling is altered but not abolished in squamous cell carcinoma (SCC) cells.
- PLK1 plays a critical role in modulating Notch signaling plasticity, potentially switching its function between tumor suppression and oncogenesis within the same tumor type.
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