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Molecular and Cellular Biology, February 2004, p. 1007-1021, Vol. 24, No. 3
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.3.1007-1021.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Suppression of PTEN Expression by NF-{kappa}B Prevents Apoptosis

Krishna Murthi Vasudevan,1 Sushma Gurumurthy,2 and Vivek M. Rangnekar1,2,3,4*

Departments of Microbiology, Immunology, and Molecular Genetics,1 Radiation Medicine,3 Graduate Center for Toxicology,2 Markey Cancer Center, University of Kentucky, Lexington, Kentucky 405364

Received 4 April 2003/ Returned for modification 27 May 2003/ Accepted 27 October 2003

NF-{kappa}B is a heterodimeric transcription activator consisting of the DNA binding subunit p50 and the transactivation subunit p65/RelA. NF-{kappa}B prevents cell death caused by tumor necrosis factor (TNF) and other genotoxic insults by directly inducing antiapoptotic target genes. We report here that the tumor suppressor PTEN, which functions as a negative regulator of phosphatidylinositol (PI)-3 kinase/Akt-mediated cell survival pathway, is down regulated by p65 but not by p50. Moreover, a subset of human lung or thyroid cancer cells expressing high levels of endogenous p65 showed decreased expression of PTEN that could be rescued by specific inhibition of the NF-{kappa}B pathway with I{kappa}B overexpression as well as with small interfering RNA directed against p65. Importantly, TNF, a potent inducer of NF-{kappa}B activity, suppressed PTEN gene expression in IKKß+/+ cells but not in IKKß-/- cells, which are deficient in the NF-{kappa}B activation pathway. These findings indicated that NF-{kappa}B activation was necessary and sufficient for inhibition of PTEN expression. The promoter, RNA, and protein levels of PTEN are down-regulated by NF-{kappa}B. The mechanism underlying suppression of PTEN expression by NF-{kappa}B was independent of p65 DNA binding or transcription function and involved sequestration of limiting pools of transcriptional coactivators CBP/p300 by p65. Restoration of PTEN expression inhibited NF-{kappa}B transcriptional activity and augmented TNF-induced apoptosis, indicating a negative regulatory loop involving PTEN and NF-{kappa}B. PTEN is, thus, a novel target whose suppression is critical for antiapoptosis by NF-{kappa}B.

* Corresponding author. Mailing address: Department of Radiation Medicine, University of Kentucky, Combs Research Building, Rm. 303, 800 Rose St., Lexington, KY 40536. Phone: (859) 257-2677. Fax: (859) 257-9608. E-mail: vmrang01{at}pop.uky.edu.

Molecular and Cellular Biology, February 2004, p. 1007-1021, Vol. 24, No. 3
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.3.1007-1021.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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