Plk5, a Polo Box Domain-Only Protein with Specific Roles in Neuron Differentiation and Glioblastoma Suppression

Abstract

Polo-like kinases (Plks) are characterized by the presence of a specific domain, known as the polo box (PBD), involved in protein-protein interactions. Plk1 to Plk4 are involved in centrosome biology as well as the regulation of mitosis, cytokinesis, and cell cycle checkpoints in response to genotoxic stress. We have analyzed here the new member of the vertebrate family, Plk5, a protein that lacks the kinase domain in humans. Plk5 does not seem to have a role in cell cycle progression; in fact, it is downregulated in proliferating cells and accumulates in quiescent cells. This protein is mostly expressed in the brain of both mice and humans, and it modulates the formation of neuritic processes upon stimulation of the brain-derived neurotrophic factor (BDNF)/nerve growth factor (NGF)-Ras pathway in neurons. The human PLK5 gene is significantly silenced in astrocytoma and glioblastoma multiforme by promoter hypermethylation, suggesting a tumor suppressor function for this gene. Indeed, overexpression of Plk5 has potent apoptotic effects in these tumor cells. Thus, Plk5 seems to have evolved as a kinase-deficient PBD-containing protein with nervous system-specific functions and tumor suppressor activity in brain cancer.

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ACKNOWLEDGMENTS

We thank Susana Temiño for technical assistance, Marta Cañamero for help in histology, and Jorge Martinalbo and Erich Nigg for preliminary assays on the overexpression of Plk5 constructs.

This work was funded by grants from the Association for International Cancer Research (AICR number 08-0188), Foundation Ramon Areces, Ministerio de Ciencia e Innovación (MICINN; SAF2009-07973), and NHGRI HG004164-01. The Cell Division and Cancer Group of the CNIO is supported by the OncoCycle Programme (S-BIO-0283-2006) from the Comunidad de Madrid, the OncoBIO Consolider-Ingenio 2010 Programme (CSD2007-00017) from the MICINN, Madrid, Spain, and the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement MitoSys (no. 241548).

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00607-10.