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PBK/TOPK promotes tumour cell proliferation through p38 MAPK activity and regulation of the DNA damage response

Oncogene volume 26, pages 3451–3461 (2007)Cite this article

Abstract

The contribution of the insulin-like growth-factor-I receptor (IGF-IR) to tumour progression is well documented. To identify new mediators of IGF-IR function in cancer, we recently isolated genes differentially expressed in cells overexpressing the IGF-IR. Among these was the serine/threonine kinase PBK/TOPK (PDZ-binding kinase/T-LAK cell-originated protein kinase), previously associated with highly proliferative cells and tissues. Here, we show that PBK is expressed at high levels in tumour cell lines compared with non-transformed cells. IGF-I could induce PBK expression only in transformed cells, whereas epidermal growth factor could induce PBK in non-transformed MCF-10A breast epithelial cells. Suppression of PBK expression using small interfering RNA did not prevent progression through the cell cycle, but caused decreased proliferation over time in culture, and reduced clonogenic growth in soft agarose. PBK knockdown impaired p38 activation after long-term stimulation with different growth factors and reduced DU145 cells motility. Suppressed PBK expression also resulted in an impaired response to DNA damage that was evident by the decreased generation of γ-H2AX, increased DNA damage and decreased cell survival. Taken together, the data indicate that PBK is necessary for appropriate activation and function of the p38 pathway by growth factors. Thus, enhanced expression of PBK may facilitate tumour growth by mediating p38 activation and by helping cells to overcome DNA damage.

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Acknowledgements

This work was funded by Science Foundation Ireland and the Health Research Board. We want to thank Dr C Morrison for kindly providing the protocol for γ-H2AX staining and for valuable comments and discussion. We are also grateful to K Tidmore for preparing the illustrations and to our colleagues for helpful discussions.

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  1. Department of Biochemistry, Cell Biology Laboratory, Biosciences Institute, National University of Ireland, Cork, Ireland

    V Ayllón & R O'Connor

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Correspondence to R O'Connor.

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Ayllón, V., O'Connor, R. PBK/TOPK promotes tumour cell proliferation through p38 MAPK activity and regulation of the DNA damage response. Oncogene 26, 3451–3461 (2007). https://doi.org/10.1038/sj.onc.1210142

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