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  • Original Paper
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Role for RhoB and PRK in the suppression of epithelial cell transformation by farnesyltransferase inhibitors

Oncogene volume 22, pages 1124–1134 (2003)Cite this article

Abstract

Recent genetic investigations have established that RhoB gain-of-function is sufficient to mediate the antitransforming effects of farnesyltransferase inhibitors (FTIs) in H-Ras-transformed fibroblast systems. In this study, we addressed the breadth and mechanism of RhoB action in epithelial cells transformed by oncoproteins which are themselves insensitive to FTI inactivation. Rat intestinal epithelial (RIE) cells transformed by activated K-Ras or Rac1 were highly sensitive to FTI-induced actin reorganization and growth inhibition, despite the inability of FTI to block prenylation of either K-Ras or Rac1. Ectopic expression of the geranylgeranylated RhoB isoform elicited in cells by FTI treatment phenocopied these effects. Analysis of RhoB effector domain mutants pointed to a role for PRK, a Rho effector kinase implicated in the physiological function of RhoB in intracellular receptor trafficking, and these findings were supported further by experiments in a fibroblast system. We propose that FTIs recruit the antioncogenic RhoB protein in the guise of RhoB-GG to interfere with signaling by pro-oncogenic Rho proteins, possibly by sequestering common exchange factors or effectors such as PRK that are important for cell transformation.

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Acknowledgements

We thank Adrienne Cox for providing RIE cells, Channing Der for the human K-Ras4B-V12 cDNA, Alan Hall for Rac1-Q61L cDNA, and Diane Sharp and Jeffrey Faust for performing flow cytometry. NR was supported by a postdoctoral research grant from the US Army Breast Cancer Research Program. This work was supported in part by NIH Grant CA82222 (GCP).

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Author notes

  1. Ping-Yao Zeng and Neena Rane: These authors contributed equally to this study.

Authors and Affiliations

  1. The Wistar Institute, Philadelphia, PA, USA

    Ping-Yao Zeng & Neena Rane

  2. Cancer Research Group, The DuPont Pharmaceuticals Company, Glenolden Laboratory, Glenolden, PA, USA

    Wei Du

  3. The Lankenau Institute for Medical Research, Wynnewood, PA, USA

    Janaki Chintapalli & George C Prendergast

  4. Department of Pathology, Anatomy, and Cell Biology, Jefferson Medical School, Thomas Jefferson University, Philadelphia, PA, USA

    George C Prendergast

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  1. Ping-Yao Zeng
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  2. Neena Rane
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  5. George C Prendergast
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Correspondence to George C Prendergast.

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Zeng, PY., Rane, N., Du, W. et al. Role for RhoB and PRK in the suppression of epithelial cell transformation by farnesyltransferase inhibitors. Oncogene 22, 1124–1134 (2003). https://doi.org/10.1038/sj.onc.1206181

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