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J. Biol. Chem., Vol. 281, Issue 27, 18878-18887, July 7, 2006

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Nuclear Localization in the Biology of the CD40 Receptor in Normal and Neoplastic Human B Lymphocytes^*

From the Department of Hematopathology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030

CD40 is a tumor necrosis factor (TNF) receptor superfamily, (TNFR; TNFRSF-5) member, that initiates important signaling pathways mediating cell growth, survival, and differentiation in B-lymphocytes. Although CD40 has been extensively studied as a plasma membrane-associated growth factor receptor, we demonstrate here that CD40 is present not only in the plasma membrane and cytoplasm but also in the nucleus of normal and neoplastic B-lymphoid cells. Confocal microscopy showed that transfected CD40-green fluorescent fusion protein entered B-cell nuclei. The CD40 protein contains a nuclear localization signal sequence that, when mutated, blocks entry of CD40 into the nucleus through the classic karyopherins (importins-/) pathway. Nuclear fractionation studies revealed the presence of CD40 protein in the nucleoplasm fraction of activated B cells, and chromatin immunoprecipitation assays demonstrated that CD40 binds to and stimulates the BLyS/BAFF promoter, another TNF family member (TNFSF-13B) involved in cell survival in the B cell lineage. Like other nuclear growth factor receptors, CD40 appears to be a transcriptional regulator and is likely to play a larger and more complex role than previously demonstrated in regulating essential growth and survival pathways in B-lymphocytes.

Received for publication, December 14, 2005 , and in revised form, April 21, 2006.

^* This work was supported by NCI, National Institutes of Health, Grants CA-RO1-100836 (to R. J. F.) and CA-16672-26 (Institution Cancer Center Support Grant) and a grant from the Lymphoma Research Foundation (to R. J. F). 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 To whom correspondence should be addressed: Dept. of Hematopathology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-563-6042; Fax: 713-794-4672; E-mail: rford{at}mdanderson.org.

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