EGFR, ErbB2 and Ras but not Src suppress RhoB expression while ectopic expression of RhoB antagonizes oncogene-mediated transformation (original) (raw)

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• Published: 01 December 2003

Oncogene volume 23, pages 1136–1145 (2004)Cite this article

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Abstract

While some low molecular weight GTPases such as Ras and RhoA contribute to malignant transformation, a closely related family member, RhoB, has tumor-suppressive activity, but little is known about its regulation by oncogenes. In this study, we show that H-Ras, N-Ras, K-Ras, EGFR and ErbB2 but not v-Src suppress RhoB promoter transcriptional activity in NIH3T3 cells and human cancer cell lines derived from lung (A-549), pancreatic (Panc-1) and cervical (C33A) tumors. The EGFR and ErbB2 suppression of RhoB promoter activity is mediated by Ras. Furthermore, Ras suppresses basal as well as 5-fluorouracil (5-FU)-induced RhoB promoter activity and RhoB protein levels. Ectopic expression of RhoB, but not the closely related family member RhoA, antagonizes the ability of EGFR, ErbB2, H-Ras, N-Ras and K-Ras but not v-Src to transform NIH3T3 cells. Furthermore, RhoB, but not RhoA, inhibits colony formation and proliferation and induces anoikis in A-549 cells and Ras-transformed NIH3T3 cells. Finally, Ras-mediated resistance to 5-FU-induced apoptosis is reversed by RhoB. These results demonstrate that RhoB expression is negatively regulated by oncogenes that are prevalent in human cancers, and that ectopic expression of RhoB antagonizes the ability of these oncogenes to induce transformation. Taken together the data suggest that certain oncogenes suppress RhoB as one of the critical steps leading to malignant transformation.

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Acknowledgements

We thank Dr Channing J Der for providing the constitutively active H-Ras61L, K-RasV12, N-RasV12 and dominant-negative N17-H-Ras, Dr Yoshiaki Monden for providing the RhoB promoter construct. We are also thankful to Dr Richard Jove for giving us SRE and v-Src cDNA constructs and Dr Noreen Luetteke for providing human EGFR, ErbB2 cDNA constructs. We also thank the Molecular Biology Core and the Flow Cytometry Core facility at the H. Lee Moffitt cancer Center and Research Institute for their technical assistance. This work is supported by NIH grant CA67771.

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Author notes

1. Frederic L Delarue
   Present address: Centre de Physiopathologie Toulouse Purpan, Dept. Innovation Therapeutique et Oncologie Moleculaire, Institute Claudius Regaud, Toulouse, France

Authors and Affiliations

1. Departments of Interdisciplinary Oncology and Biochemistry & Molecular Biology, Drug Discovery Program, H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, FL, USA
   Kun Jiang, Frederic L Delarue & Saïd M Sebti

Authors

1. Kun Jiang
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2. Frederic L Delarue
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3. Saïd M Sebti
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Correspondence toSaïd M Sebti.

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Jiang, K., Delarue, F. & Sebti, S. EGFR, ErbB2 and Ras but not Src suppress RhoB expression while ectopic expression of RhoB antagonizes oncogene-mediated transformation.Oncogene 23, 1136–1145 (2004). https://doi.org/10.1038/sj.onc.1207236

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• Received: 23 July 2003
• Revised: 22 September 2003
• Accepted: 22 September 2003
• Published: 01 December 2003
• Issue Date: 05 February 2004
• DOI: https://doi.org/10.1038/sj.onc.1207236

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