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J. Biol. Chem., Vol. 279, Issue 6, 4285-4291, February 6, 2004

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Down-regulation of the Tumor Suppressor PTEN by the Tumor Necrosis Factor-/Nuclear Factor-B (NF-B)-inducing Kinase/NF-B Pathway Is Linked to a Default IB- Autoregulatory Loop^*

Sunghoon Kim¶, Claire Domon-Dell¶||**, Junghee Kang, Dai H. Chung, Jean-Noel Freund||, and B. Mark Evers

From the Department of Surgery and Sealy Center for Cancer Cell Biology, The University of Texas Medical Branch, Galveston, Texas 77555-0536 and ^||INSERM, Unité 381, 67200 Strasbourg, France

The PTEN (phosphatase and tensin homolog deleted on chromosome ten) tumor suppressor gene affects multiple cellular processes including cell growth, proliferation, and cell migration by antagonizing phosphatidylinositol 3-kinase (PI3K). However, mechanisms by which PTEN expression is regulated have not been studied extensively. Similar to PTEN, tumor necrosis factor- (TNF-) affects a wide spectrum of diseases including inflammatory processes and cancer by acting as a mediator of apoptosis, inflammation, and immunity. In this study, we show that treatment of cancer cell lines with TNF- decreases PTEN expression. In addition, overexpression of TNF- downstream signaling targets, nuclear factor-B (NF-B)-inducing kinase (NIK) and p65 nuclear factor NF-B, lowers PTEN expression, suggesting that TNF--induced down-regulation of PTEN is mediated through a TNF-/NIK/NF-B pathway. Down-regulation of PTEN by NIK/NF-B results in activation of the PI3K/Akt pathway and augmentation of TNF--induced PI3K/Akt stimulation. Importantly, we demonstrate that this effect is associated with a lack of an inhibitor of B (IB)- autoregulatory loop. Moreover, these findings suggest the interaction between PI3K/Akt and NF-B via transcriptional regulation of PTEN and offer one possible explanation for increased tumorigenesis in systems in which NF-B is chronically activated. In such a tumor system, these findings suggest a positive feedback loop whereby Akt activation of NF-B further stimulates Akt via down-regulation of the PI3K inhibitor PTEN.

Received for publication, July 31, 2003 , and in revised form, October 17, 2003.

^* This work was supported in part by National Institutes of Health Grants R01-DK48498, R37-AG10885, and R01-DK35608 and by a grant from the Association Francois Aupetit. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of Texas Gulf Coast Digestive Disease Center Pilot Feasibility Grant P30-DK56338.

^¶ These authors contributed equally to this work.

^** Recipient of a fellowship from the Foundation Ipsen.

To whom correspondence should be addressed: Dept. of Surgery, The University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0536. Tel.: 409-772-5612; Fax: 409-747-4819; E-mail: mevers{at}utmb.edu.

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