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.

PLK1 targets NOTCH1 during DNA damage and mitotic progression / DE BLASIO, Carlo; Zonfrilli, A.; Franchitto, Matteo; Mariano, G.; Cialfi, S.; Verma, Nagendra; Checquolo, S.; Bellavia, D.; Palermo, R.; Benelli, D.; Screpanti, I.; Talora, C.. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - 294:47(2019), pp. 17941-17950. [10.1074/jbc.RA119.009881]

PLK1 targets NOTCH1 during DNA damage and mitotic progression

Carlo De Blasio;Zonfrilli A.;FRANCHITTO, MATTEO;Mariano G.;Cialfi S.;VERMA, NAGENDRA;Checquolo S.;Bellavia D.;Palermo R.;Benelli D.;Screpanti I.;Talora C.
2019

Abstract

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.
2019
Arsenic; DNA damage; DNA damage response; Notch; Notch pathway; PLK1; cancer biology; cell cycle; cell transformation; stress response
01 Pubblicazione su rivista::01a Articolo in rivista
PLK1 targets NOTCH1 during DNA damage and mitotic progression / DE BLASIO, Carlo; Zonfrilli, A.; Franchitto, Matteo; Mariano, G.; Cialfi, S.; Verma, Nagendra; Checquolo, S.; Bellavia, D.; Palermo, R.; Benelli, D.; Screpanti, I.; Talora, C.. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - 294:47(2019), pp. 17941-17950. [10.1074/jbc.RA119.009881]
File allegati a questo prodotto
File Dimensione Formato  
De Blasio_PLK1_2019.pdf

accesso aperto

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Creative commons
Dimensione 1.71 MB
Formato Adobe PDF
1.71 MB Adobe PDF

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1345708
Citazioni
  • ???jsp.display-item.citation.pmc??? 8
  • Scopus 15
  • ???jsp.display-item.citation.isi??? 15
social impact