Abstract
Polo-like kinases (PLKs) belong to a five-membered family of highly conserved serine/threonine kinases (PLK1-5) that play differentiated and essential roles as key mitotic kinases and cell cycle regulators and with this in proliferation and cellular growth. Besides, evidence is accumulating for complex and vital non-mitotic functions of PLKs. Dysregulation of PLKs is widely associated with tumorigenesis and by this, PLKs have gained increasing significance as attractive targets in cancer with diagnostic, prognostic and therapeutic potential. PLK1 has proved to have strong clinical relevance as it was found to be over-expressed in different cancer types and linked to poor patient prognosis. Targeting the diverse functions of PLKs (tumor suppressor, oncogenic) are currently at the center of numerous investigations in particular with the inhibition of PLK1 and PLK4, respectively in multiple cancer trials. Functions of PLKs and the effects of their inhibition have been extensively studied in cancer cell culture models but information is rare on how these drugs affect benign tissues and organs. As a step further towards clinical application as cancer targets, mouse models therefore play a central role. Modelling PLK function in animal models, e.g., by gene disruption or by treatment with small molecule PLK inhibitors offers promising possibilities to unveil the biological significance of PLKs in cancer maintenance and progression and give important information on PLKs’ applicability as cancer targets. In this review we aim at summarizing the approaches of modelling PLK function in mice so far with a special glimpse on the significance of PLKs in ovarian cancer and of orthotopic cancer models used in this fatal malignancy.
Highlights
The founding name polo deduces from the effect of the gene-knockout first described in Drosophila melanogaster in form of abnormal spindle poles during mitosis [1]
polo-like kinase 1 (PLK1) and PLK4 have been considered as oncogenes whereas tumorsuppressive functions are attributed to PLK2, PLK3, and PLK5
PLK3 is critically involved in oncogenesis and dysregulated expression of PLK3 is found in a variety of tumors
Summary
The founding name polo deduces from the effect of the gene-knockout first described in Drosophila melanogaster in form of abnormal spindle poles during mitosis [1]. The multiplicity of substrates of PLK1 beyond mitosis (for reviews see [31,46,47]) suggests much more complex roles in cell cycle regulation and underlines vital interphaserelated cellular functions far beyond the traditional mitotic ones which are controlling microtubules in the centrosomes, the spindle and the kinetochore. These non-mitotic functions include ciliogenesis, DNA replication, transcription and translation, stress signaling. DNA damage or microtubule disruption, inducing G1 cell cycle arrest and apoptotic cell death [95], suggesting a cell-protective function
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