RhoB facilitates c-Myc turnover by supporting efficient nuclear accumulation of GSK-3.
The small GTPase RhoB suppresses cancer in part by limiting cell proliferation. However, the mechanisms it uses to achieve this are poorly understood. Recent studies link RhoB to trafficking of Akt, which through its regulation of glycogen synthase kinase-3 (GSK-3) has an important role in controlling the stability of the c-Myc oncoprotein. c-Myc stabilization may be a root feature of human tumorigenesis as it phenocopies an essential contribution of SV40 small T antigen in human cell transformation. In this study we show that RhoB directs efficient turnover of c-Myc in established or transformed mouse fibroblasts and that the attenuation of RhoB which occurs commonly in human cancer is a sufficient cause to elevate c-Myc levels. Increased levels of c-Myc elicited by RhoB deletion increased the proliferation of nullizygous cells, whereas restoring RhoB in null cells decreased the stability of c-Myc and restrained cell proliferation. Mechanistic analyses indicated that RhoB facilitated nuclear accumulation of GSK-3 and GSK-3-mediated phosphorylation of c-Myc T58, the critical site for ubiquitination and degradation of c-Myc. RhoB deletion restricted nuclear localization of GSK-3, reduced T58 phosphorylation, and stabilized c-Myc. These effects were not associated with changes in phosphorylation or localization of Akt, however, differences were observed in phosphorylation and localization of the GSK-3 regulatory Akt-related kinase, serum- and glucocorticoid-inducible protein kinase (SGK). The ability of RhoB to support GSK-3-dependent turnover of c-Myc offers a mechanism by which RhoB acts to limit the proliferation of neoplastically transformed cells.
Huang
M
M
Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.
Kamasani
U
U
Prendergast
G C
GC
D000818:Animals; D018929:Cell Culture Techniques; D002467:Cell Nucleus / Q000201:enzymology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D005347:Fibroblasts; D038362:Glycogen Synthase Kinase 3 / Q000493:pharmacokinetics*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000503:physiopathology*; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D014170:Transformation, Genetic; D020743:rhoB GTP-Binding Protein / Q000502:physiology*
D016271:Proto-Oncogene Proteins c-myc; D038362:Glycogen Synthase Kinase 3; D020743:rhoB GTP-Binding Protein