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J. Biol. Chem., Vol. 283, Issue 22, 15399-15408, May 30, 2008

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The Lymphotoxin-β Receptor Is an Upstream Activator of NF-B-mediated Transcription in Melanoma Cells^*

Punita Dhawan¹, Yingjun Su¹, Yee Mon Thu, Yingchun Yu, Paige Baugher, Darrel L. Ellis^¶, Tammy Sobolik-Delmaire, Mark Kelley, Timothy C. Cheung^||, Carl F. Ware^||, and Ann Richmond^**2

From the ^**Department of Veterans Affairs, Nashville, Tennessee 37212,Department of Cancer Biology, Surgical Oncology Research Laboratories, Department of Surgery, and ^¶Division of Dermatology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, and ^||Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121

The pleiotropic transcription factor nuclear factor-B (NF-B (p50/p65)) regulates the transcription of genes involved in the modulation of cell proliferation, apoptosis, and oncogenesis. Furthermore, a host of solid and hematopoietic tumor types exhibit constitutive activation of NF-B (Basseres, D. S., and Baldwin, A. S. (2006) 25, 6817-6830). However, the mechanism for this constitutive activation of NF-B has not been elucidated in the tumors. We have previously shown that NF-B-inducing kinase (NIK) protein and its association with Inhibitor of B kinase β are elevated in melanoma cells compared with their normal counterpart, leading to constitutive activation of NF-B. Moreover, expression of dominant negative NIK blocked this base-line NF-B activity in melanoma cells. Of the three receptors that require NIK for activation of NF-B, only the lymphotoxin-β receptor (LTβ-R) is expressed in melanoma. We show in this manuscript that for melanoma there is a strong relationship between expression of the LTβ-R and constitutive NF-B transcriptional activity. Moreover, we show that activation of the LTβ-R can drive NF-B activity to regulate gene expression that leads to enhanced cell growth. The inhibition by LTβ-R shRNA resulted in decreased NF-B promoter activity, decreased growth, and decreased invasiveness as compared with control. These results indicate that the LTβ-R constitutively induces NF-B activation, and this event may be associated with autonomous growth of melanoma cells.

Received for publication, October 4, 2007 , and in revised form, March 4, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants CA56704, CA098807, and CA68485. This work was also supported by a Department of Veterans Affairs Senior Career Scientist award (to A. R.), National Institutes of Health Grants SP30 AR1943 (to the Skin Disease Research Center) and T30 HL 07751 (to Y. S.), and by the Ingram Family Charitable Trust. 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 These two authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Cancer Biology, PRB 432, Vanderbilt University School of Medicine, 23rd Ave. S at Pierce, Nashville, TN 37232. Tel.: 615-343-7777; Fax: 615-936-2911; E-mail: ann.richmond{at}vanderbilt.edu.

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