Plk1 overexpression suppresses tumor development by inducing chromosomal instability

Autor: Nicholas McGranahan, Sharavan Vishaan Venkateswaran, Aicha El Bakkali, Beatriz Escobar, Manuel Sanclemente, Guillermo de Cárcer, Lorena Salgueiro, Marcos Malumbres, Pablo Montanes, Kalman Somogyi, Rocio Sotillo, Alba de Martino, Konstantina Rowald
Jazyk: angličtina
Rok vydání: 2018
Předmět:
DOI: 10.1101/285635
Popis: Polo-like kinase 1 (Plk1) is a protein kinase currently considered as an attractive cancer target due to its critical role in the cell division cycle. Plk1 is overexpressed in a wide spectrum of human tumors, being frequently considered as an oncogene. However, its contribution to tumor development is unclear. Using a new inducible knock-in mouse model we report here that Plk1 overexpression does not favor cell proliferation but rather results in abnormal chromosome segregation and cytokinesis, leading to the formation of polyploid cells with reduced proliferative potential. Mechanistically, these cytokinesis defects correlate with defective loading of Cep55 and ESCRT complexes to the abscission bridge during cytokinesis in a Plk1 kinase-dependent manner. In vivo, elevated levels of Plk1 markedly prevent the development of mammary gland tumors induced either by KrasG12D or Her2, in the presence of increased rates of chromosome instability. In patients, higher Plk1 expression levels are associated with significantly increased overall survival in breast cancer subtypes. These data suggest that, despite the therapeutic benefits of inhibiting Plk1 due to its essential role in tumor cell cycles, Plk1 overexpression has tumor suppressive properties by perturbing mitotic progression and cytokinesis.
Databáze: OpenAIRE