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J. Biol. Chem., Vol. 282, Issue 6, 3507-3519, February 9, 2007

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Mitogen-activated Protein Kinase Kinase-4 Promotes Cell Survival by Decreasing PTEN Expression through an NFB-dependent Pathway^*

Dianren Xia, Harish Srinivas, Young-ho Ahn, Gautam Sethi, Xiaoyang Sheng^¶, W. K. Alfred Yung^¶, Qianghua Xia^||, Paul J. Chiao^||, Heetae Kim^**, Powel H. Brown^**, Ignacio I. Wistuba, Bharat B. Aggarwal, and Jonathan M. Kurie¹

From the Departments of Thoracic/Head and Neck Medical Oncology, Experimental Therapeutics, ^¶Neuro-Oncology, and ^||Surgical Oncology, University of Texas M. D. Anderson Cancer Center and ^**Breast Center and Department of Medicine, Baylor College of Medicine, Houston, Texas 77030

Mitogen-activated protein kinase kinase-4 (MKK4/SEK1) cooperates with phosphatidylinositol 3-kinase to maintain the survival of non-small cell lung cancer (NSCLC) cells, but the biochemical basis of this phenomenon has not been elucidated. Here we used genetic approaches to modulate MKK4 expression in mouse embryo fibroblasts (MEF cells) and NSCLC cells to identify prosurvival signals downstream of MKK4. Relative to wild-type MEF cells, MKK4-null MEF cells were highly susceptible to apoptosis by LY294002, paclitaxel, or serum starvation. MKK4 promoted the survival of MEF cells by decreasing the expression of phosphatase and tensin homologue deleted from chromosome 10 (PTEN). MKK4 inhibited PTEN transcription by activating NFB, a transcriptional suppressor of PTEN. MKK4 was required for nuclear translocation of RelA/p65 and processing of the NFB2 precursor (p100) into the mature form (p52). Studies on a panel of NSCLC cell lines revealed a subset with high MKK4/high NFB/low PTEN that was relatively resistant to apoptosis. Thus, MKK4 promotes cell survival by activating phosphatidylinositol 3-kinase through an NFB/PTEN-dependent pathway.

Received for publication, October 30, 2006 , and in revised form, December 1, 2006.

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence should be addressed: University of Texas M. D. Anderson Cancer Center, Dept. of Thoracic/Head and Neck Medical Oncology-Unit 432, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-792-6363; Fax: 713-792-1220; E-mail: jkurie{at}mdanderson.org.

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