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Keratinocyte growth factor activates p38 MAPK to induce stress fibre formation in human prostate DU145 cells

Abstract

FGF7/Keratinocyte growth factor (KGF) regulates the differentiation and development of the prostate epithelium, while over-expression of FGF8 and FGF1 are implicated in carcinogenesis of the prostate. We tested the hypothesis that different members of the FGF family function through different signalling molecules. In prostate DU145 cells, both FGF1 and FGF2 activated ERK1/2 potently and p38 moderately. KGF was however most efficient in inducing p38 activities but had no effect on ERK1/2 function. JNK and STAT activities were not induced by FGFs in prostate cells. In vitro expression of the transcription factors Elk-1 and MEF2A (substrates for ERK1/2 and p38, respectively) for functional quantification, confirmed the pattern of FGF-induced MAPK activations in COS-7 cells. Furthermore, KGF was more efficient than FGF1 and FGF2 in inducing actin stress fibres, and the specific p38 inhibitor SB202190 completely abolished this in a dose-dependent manner. The MEK1/2 inhibitor, U0126, had no effect on FGF-induced stress fibre formation. This study demonstrates the selective activation of MAPK family members by FGFs resulting in activation of transcription factors and stress fibre formation. As multiple FGFs are over-expressed in human prostate cancer, characterization of the distinct signalling pathway by FGFs may reveal new specific targets for therapy.

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Abbreviations

FGF:

fibroblast growth factor

KGF:

keratinocyte growth factor

FGFR:

FGF receptor

MAPK:

mitogen-activated protein kinase

ERK:

extracellular signal-regulated protein kinase

JNK:

c-Jun N-terminal kinase

STATs:

signal transducers and activators of transcription

PLC-γ:

phospholipase C gamma

FRS2:

FGFR substrate-2

BPH:

benign prostatic hyperplasia, FCS, foetal calf serum

MEF2A:

Muscle enhancer factor-2A

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Acknowledgements

We gratefully acknowledge the William Edmund Harker Foundation, University of Newcastle upon Tyne for funding this project. We thank Dr AD Sharrocks (Manchester University, UK) for providing the Elk-1-FLAG and GAL-MEF2A/ΔD expression plasmids and Dr T Booth (University of Newcastle, UK) for assistance with all confocal laser imaging.

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Correspondence to Hing Y Leung.

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Mehta, P., Robson, C., Neal, D. et al. Keratinocyte growth factor activates p38 MAPK to induce stress fibre formation in human prostate DU145 cells. Oncogene 20, 5359–5365 (2001). https://doi.org/10.1038/sj.onc.1204688

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