title: AKT Activation by Pdcd4 Knockdown Up-Regulates Cyclin D1 Expression and Promotes Cell Proliferation.
abstract: Programmed cell death 4 (Pdcd4), a novel tumor suppressor, inhibits neoplastic transformation and tumor invasion. In this study, the authors found that knockdown of Pdcd4 promoted cell proliferation and up-regulated cyclin D1 expression. Previously, the authors demonstrated that Pdcd4 knockdown activated NF-κB-dependent transcription. Mutations of NF-κB binding sites on the cyclin D1 promoter attenuated the cyclin D1 promoter activity induced by Pdcd4 knockdown. In addition, knockdown of NF-κB/IκB kinase (IKK) α or IKKβ, the kinase regulating NF-κB activation, inhibited cyclin D1 promoter activity and cyclin D1 expression, indicating that up-regulation of cyclin D1 by Pdcd4 knockdown is contributed, at least in part, by NF-κB activation. To investigate the mechanism of how Pdcd4 knockdown activates NF-κB, the authors found that the levels of AKT phosphorylation and AKT kinase activity were increased in the Pdcd4 knockdown cells. Conversely, ectopic expression of Pdcd4 inhibited AKT phosphorylation and cyclin D1 expression, suggesting that Pdcd4 regulates AKT activity and cyclin D1 expression. Furthermore, knockdown of AKT in the Pdcd4 knockdown cells inhibited IKK phosphorylation, NF-κB activation, cyclin D1 promoter activity, and cyclin D1 expression as well as cell proliferation. Taken together, these findings suggest that activation of NF-κB by Pdcd4 knockdown through AKT contributes to the elevated expression of cyclin D1, thus providing new insights into how loss of Pdcd4 expression promotes tumor development.
authors.affiliation: Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY, USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Guo
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Li
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.forename: Hsin-Sheng
authors.initials: HS
authors.lastname: Yang