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Antiapoptotic Effect of Serum and Glucocorticoid-Inducible Protein Kinase Is Mediated by Novel Mechanism Activating IB Kinase

Departments of ¹ Internal Medicine, ² Pharmacology and Toxicology, and ³ Human Biological Chemistry & Genetics, University of Texas Medical Branch, Galveston, Texas

Requests for reprints: Jie Du, Department of Internal Medicine, 9.138 Medical Research Building, University of Texas Medical Branch, Galveston, TX 77555-1064. Phone: 409-772-3362; Fax: 409-747-0692; E-mail: jidu{at}utmb.edu.

Serum and glucocorticoid inducible protein kinase (SGK) plays a crucial role in promoting cell survival, but the mechanisms for this response are not clear. We show that SGK is involved in the regulation of apoptosis in breast cancer cells by modulating the transcriptional activity of nuclear transcription factor B (NF-B). High levels of SGK expression were observed in human breast cancer samples. When SGK was reduced the apoptotic rate increased, and increased SGK activity prevents serum withdrawal–induced apoptosis. SGK-induced cell survival was abolished by a dominant-negative form of IB kinase ß (IKKß, K44A) or a null mutation of IKKß in mouse embryonic fibroblast cells indicating involvement of the NF-B pathway. Serum-induced SGK or increased expression of SGK activated NF-B transcriptional activity, whereas small interference RNA to SGK blocked NF-B activity. Coexpression of SGK and IKKß significantly increased the activation of NF-B (versus expression of IKKß alone). Expression of dominant-negative IKKß K44A, IB AA, and kinase-dead SGK (127KM) blocked the ability of SGK to stimulate NF-B activity, suggesting that IKKß is a target of SGK. We also show that SGK enhances the ability of IKKß to phosphorylate endogenous IB in cells or recombinant glutathione S-transferase-IB in vitro and increases IB degradation; SGK physically associates with and activates IKKß in MDA231 cells via phosphorylation of Ser¹⁸¹ in IKKß. Taken together, we conclude that SGK acts as an oncogene in breast cancer cells through activation of the IKK-NF-B pathway, thereby preventing apoptosis. Blocking SGK expression/activity represents a potential therapeutic approach for breast cancer treatment.

Key Words: Breast cancer • Signal transduction • Survival factors • Transcriptional control of apoptosis

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