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Molecular and Cellular Biology, June 2004, p. 5565-5576, Vol. 24, No. 12
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.12.5565-5576.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Akt Mediates Ras Downregulation of RhoB, a Suppressor of Transformation, Invasion, and Metastasis

Kun Jiang,1,2,3 Jiazhi Sun,1,2,3,{dagger} Jin Cheng,4 Julie Y. Djeu,2 Sheng Wei,2 and Saïd Sebti1,2,3*

Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute,1 Departments of Interdisciplinary Oncology,2 Biochemistry and Molecular Biology,3 and Pathology, University of South Florida, Tampa, Florida 336124

Received 15 October 2003/ Returned for modification 26 November 2003/ Accepted 15 March 2004

Although recent evidence supports a tumor-suppressive role for the GTPase RhoB, little is known about its regulation by signal transduction pathways. Here we demonstrate that Ras downregulates RhoB expression by a phosphatidylinositol 3-kinase (PI3K)- and Akt- but not Mek-dependent mechanism. Furthermore, genetic and pharmacological blockade of PI3K/Akt results in upregulation of RhoB expression. We also provide evidence for the importance of the downregulation of RhoB in oncogenesis by demonstrating that RhoB antagonizes Ras/PI3K/Akt malignancy. Ectopic expression of RhoB, but not the close relative RhoA, inhibits Ras, PI3K, and Akt induction of transformation, migration, and invasion and induces apoptosis and anoikis. Finally, RhoB inhibits melanoma metastasis to the lung in a mouse model. These studies identify suppression of RhoB as a mechanism by which the Ras/PI3K/Akt pathway induces tumor survival, transformation, invasion, and metastasis.

* Corresponding author. Mailing address: Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., MRC-DRDIS, Tampa, FL 33612. Phone: (813) 979-6734. Fax: (813) 979-6748. E-mail: sebti{at}moffitt.usf.edu.

{dagger} Present address: College of Medicine, Pennsylvania State University, Hershey, PA 17033.

Molecular and Cellular Biology, June 2004, p. 5565-5576, Vol. 24, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.12.5565-5576.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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