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Targeted Deletion of MKK4 Gene Potentiates TNF-Induced Apoptosis through the Down-Regulation of NF-B Activation and NF-B-Regulated Antiapoptotic Gene Products¹

Gautam Sethi^*, Kwang Seok Ahn^*, Dianren Xia, Jonathan M. Kurie and Bharat B. Aggarwal^2,*

^* Cytokine Research Laboratory, Department of Experimental Therapeutics, and Department of Thoracic, Head and Neck Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030

MAPK kinase 4 (MKK4) is a dual-specificity kinase that activates both JNK and p38 MAPK. However, the mechanism by which MKK4 regulates TNF-induced apoptosis is not fully understood. Therefore, we used fibroblasts derived from MKK4 gene-deleted (MKK4-KO) mice to determine the role of this kinase in TNF signaling. We found that when compared with the wild-type cells, deletion of MKK4 gene enhanced TNF-induced apoptosis, and this correlated with down-regulation of TNF-induced cell-proliferative (COX-2 and cyclin D1) and antiapoptotic (survivin, IAP1, XIAP, Bcl-2, Bcl-x_L, and cFLIP) gene products, all regulated by NF-B. Indeed we found that TNF-induced NF-B activation was abrogated in MKK4 gene-deleted cells, as determined by DNA binding. Further investigation revealed that TNF-induced IB kinase activation, IB phosphorylation, IB degradation, and p65 nuclear translocation were all suppressed in MKK4-KO cells. NF-B reporter assay revealed that NF-B activation induced by TNF, TNFR1, TRADD, TRAF2, NIK, and IB kinase was modulated in gene-deleted cells. Overall, our results indicate that MKK4 plays a central role in TNF-induced apoptosis through the regulation of NF-B-regulated gene products.

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.

¹ This work was supported by a grant from the Clayton Foundation for Research (to B.B.A.), by Grant PO1 CA91844 on lung chemoprevention from the National Institutes of Health (to B.B.A.), and by Grant P50 CA97007 from the National Institutes of Health Head and Neck SPORE Program (to B.B.A.). Dr. Aggarwal is the Ransom Horne, Jr., Professor of Cancer Research.

² Address correspondence and reprint requests to Dr. Bharat B. Aggarwal, Cytokine Research Laboratory, Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail address: aggarwal{at}mdanderson.org

³ Abbreviations used in this paper: MKK, MAPK kinase; IKK, IB kinase; PARP, poly(ADP-ribose) polymerase; SEAP, secretory alkaline phosphatase; COX-2, cyclooxygenase-2; MMP-9, matrix metalloproteinase-9; TRADD, TNFR-associated death domain; TRAF, TNFR-associated factor; NIK, NF-B-inducing kinase; IAP, inhibitor of apoptosis protein; cFLIP, cellular FLIP; CSC, cigarette smoke condensate.

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The JI 2007 179: 1411-1412. [Full Text]