Plk1 overexpression induces chromosomal instability and suppresses tumor development

Autor: Nicholas McGranahan, Guillermo de Cárcer, Konstantina Rowald, Beatriz Escobar, Rocio Sotillo, Alba de Martino, Pablo Montanes, Marcos Malumbres, Sharavan Vishaan Venkateswaran, Aicha El Bakkali, Kalman Somogyi, Manuel Sanclemente, Lorena Salgueiro
Přispěvatelé: Fundación Ramón Areces, European Research Council, Howard Hughes Medical Institute, Asociación Española Contra el Cáncer, Ministerio de Economía y Competitividad (España), Comunidad de Madrid (España), Worldwide Cancer Research
Rok vydání: 2018
Předmět:
0301 basic medicine
Carcinogenesis
General Physics and Astronomy
Cell Cycle Proteins
Polo-like kinase
THERAPEUTIC TARGETS
Mice
MAMMALIAN-CELLS
Chromosome Segregation
Chromosome instability
lcsh:Science
Multidisciplinary
Kinase
Nuclear Proteins
POLO-LIKE KINASE
ANTICANCER THERAPY
3. Good health
Cell Transformation
Neoplastic
Female
EXPRESSION
Science
Breast Neoplasms
Protein Serine-Threonine Kinases
Biology
ESCRT MACHINERY
PLK1
Article
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Cell Line
Tumor
Chromosomal Instability
Proto-Oncogene Proteins
medicine
Animals
Humans
BREAST-CANCER
Cell Proliferation
Cytokinesis
Centrosome
Endosomal Sorting Complexes Required for Transport
Oncogene
ANEUPLOIDY
Cell growth
Cancer
Oncogenes
General Chemistry
Fibroblasts
Embryo
Mammalian
medicine.disease
Disease Models
Animal
MICE
030104 developmental biology
Cancer research
lcsh:Q
SCREEN
Zdroj: Nature Communications, Vol 9, Iss 1, Pp 1-14 (2018)
Repisalud
Instituto de Salud Carlos III (ISCIII)
Nature Communications
ISSN: 2041-1723
Popis: 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.
PLK1 is a mitotic regulator overexpressed in cancer; however, whether this overexpression causally contributes to tumor development is unclear. Here the authors produce an inducible mouse model to overexpress PLK1 and show that actually this can act as a tumor suppressor by perturbing mitotic progression and cytokinesis.
Databáze: OpenAIRE
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