Abstract
Polo-like kinase 1 (Plk1) is overexpressed in a wide spectrum of human tumors, being frequently considered as an oncogene and an attractive cancer target. However, its contribution to tumor development is unclear. Using a new inducible knock-in mouse model we report here that Plk1 overexpression results in abnormal chromosome segregation and cytokinesis, generating polyploid cells with reduced proliferative potential. Mechanistically, these cytokinesis defects correlate with defective loading of Cep55 and ESCRT complexes to the abscission bridge, in a Plk1 kinase-dependent manner. In vivo, Plk1 overexpression prevents the development of Kras-induced and Her2-induced mammary gland tumors, in the presence of increased rates of chromosome instability. In patients, Plk1 overexpression correlates with improved survival in specific breast cancer subtypes. Therefore, 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.
Highlights
Polo-like kinase 1 (Plk1) is overexpressed in a wide spectrum of human tumors, being frequently considered as an oncogene and an attractive cancer target
We found that Plk[1] overexpression functions as a tumor suppressor both in vitro and in vivo
The FLAG-Plk[1] cDNA is expressed under the tetracycline-inducible operator sequences and it is induced after the activation of the reverse tetracycline transactivator with the tetracycline derivative doxycycline (Dox; Fig. 1a)
Summary
Polo-like kinase 1 (Plk1) is overexpressed in a wide spectrum of human tumors, being frequently considered as an oncogene and an attractive cancer target. Using a new inducible knock-in mouse model we report here that Plk[1] overexpression results in abnormal chromosome segregation and cytokinesis, generating polyploid cells with reduced proliferative potential. These cytokinesis defects correlate with defective loading of Cep[55] and ESCRT complexes to the abscission bridge, in a Plk[1] kinase-dependent manner. Plk[1] induction has been proposed to play a role at early stages during the progression of certain carcinomas and its overexpression inversely correlates with the survival rate of patients with non-small cell lung, head and neck, and esophageal cancer, among others[15,16,17]. Increased levels of Plk[1] in breast cancer patients is associated with better prognosis
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