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Phorbol esters inhibit fibroblast growth factor-2-stimulated fibroblast proliferation by a p38 MAP kinase dependent pathway

Oncogene volume 21, pages 1978–1988 (2002)Cite this article

Abstract

Treatment of fibroblasts with the phorbol ester, 12-O-tetradecanoyl phorbol 13-acetate (TPA), specifically inhibits fibroblast growth factor-2 (FGF-2) induced proliferation. TPA treatment has little or no effect on FGF receptor activation but specifically inhibits the activation of p38 MAPK but not other downstream signaling pathways implicated in cell proliferation. p38 MAPK was recently shown to be required for the FGF-2-stimulated proliferation of fibroblasts. The effect of TPA on both p38 MAPK activation and cell proliferation can be reversed by treatment with the PKC inhibitor Go6983. The TPA-mediated inhibition of p38 MAPK activation requires phosphatase activity and is at least partially mediated by ERKs since it is reduced by treatment with the MEK inhibitor PD98059. In contrast, the FGF-2-stimulated differentiation of PC12 cells, which express the same FGF receptor as Swiss 3T3 fibroblasts, is not affected by TPA treatment, consistent with a lack of involvement of p38 MAPK activity in this process. These data indicate that the effects of TPA treatment on cellular function are not only cell type but also stimulus specific and are dependent upon the distinct pathways activated downstream of each stimulus.

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Abbreviations

FGF:

fibroblast growth factor

FGFR:

fibroblast growth factor receptor

MAPK:

mitogen-activated protein kinase

ERK:

extracellular signal-regulated kinase

MEK:

mitogen-activated protein/ERK kinase

PAGE:

polyacrylamide gel electrophoresis, PBS, phosphate-buffered saline

TBS:

Tris-buffered saline

PMSF:

phenylmethylsulfonyl fluoride

DMEM:

Dulbecco's modified minimal essential medium

MOPS:

4-morpholinepropanesulfonic acid

TPA:

12-O-tetradecanoyl phorbol 13-acetate

PKC:

protein kinase C

MKP:

MAP kinase phosphatase

PI3K:

phosphatidylinositol 3-kinase

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Acknowledgements

The author would like to thank Dr David Schubert for helpful discussions and Lori Huska and Cathy Dabney for help in preparing the figures. This work was supported by NIH grant GM54604.

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  1. Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, CA, USA

    Pamela Maher

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Correspondence to Pamela Maher.

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Maher, P. Phorbol esters inhibit fibroblast growth factor-2-stimulated fibroblast proliferation by a p38 MAP kinase dependent pathway. Oncogene 21, 1978–1988 (2002). https://doi.org/10.1038/sj.onc.1205268

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