PLK1 targets NOTCH1 during DNA damage and mitotic progression

• Published in: The Journal of biological chemistry Vol. 294; no. 47; pp. 17941 - 17950
• Main Authors: De Blasio, Carlo, Zonfrilli, Azzurra, Franchitto, Matteo, Mariano, Germano, Cialfi, Samantha, Verma, Nagendra, Checquolo, Saula, Bellavia, Diana, Palermo, Rocco, Benelli, Dario, Screpanti, Isabella, Talora, Claudio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.11.2019; American Society for Biochemistry and Molecular Biology
• Subjects: Apoptosis - drug effects; Arsenic; Arsenites - toxicity; cancer biology; Cell Biology; cell cycle; Cell Cycle Checkpoints - drug effects; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - metabolism; Cell Line; Cell Line, Tumor; Cell Proliferation - drug effects; cell transformation; Cytokines - metabolism; DNA Damage; DNA damage response; Down-Regulation - drug effects; G2 Phase - drug effects; Humans; Inflammation Mediators - metabolism; Keratinocytes - drug effects; Keratinocytes - metabolism; Mitosis - drug effects; Notch; Notch pathway; Phosphorylation - drug effects; PLK1; Polo-Like Kinase 1; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Proteolysis - drug effects; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - metabolism; Receptor, Notch1 - metabolism; stress response; Substrate Specificity - drug effects; cell transformation; Notch pathway; stress response; Arsenic; DNA damage response; cell cycle; DNA damage; Notch; PLK1; cancer biology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA119.009881

Notch signaling plays a complex role in carcinogenesis, and its signaling pathway has both tumor suppressor and oncogenic components. To identify regulators that might control this dual activity of NOTCH1, we screened a chemical library targeting kinases and identified Polo-like kinase 1 (PLK1) as one of the kinases involved in arsenite-induced NOTCH1 down-modulation. As PLK1 activity drives mitotic entry but also is inhibited after DNA damage, we investigated the PLK1-NOTCH1 interplay in the G2 phase of the cell cycle and in response to DNA damage. Here, we found that PLK1 regulates NOTCH1 expression at G2/M transition. However, when cells in G2 phase are challenged with DNA damage, PLK1 is inhibited to prevent entry into mitosis. Interestingly, we found that the interaction between NOTCH1 and PLK1 is functionally important during the DNA damage response, as we found that whereas PLK1 activity is inhibited, NOTCH1 expression is maintained during DNA damage response. During genotoxic stress, cellular transformation requires that promitotic activity must override DNA damage checkpoint signaling to drive proliferation. Interestingly, we found that arsenite-induced genotoxic stress causes a PLK1-dependent signaling response that antagonizes the involvement of NOTCH1 in the DNA damage checkpoint. Taken together, our data provide evidence that Notch signaling is altered but not abolished in SCC cells. Thus, it is also important to recognize that Notch plasticity might be modulated and could represent a key determinant to switch on/off either the oncogenic or tumor suppressor function of Notch signaling in a single type of tumor.