Nuclear localization in the biology of the CD40 receptor in normal and neoplastic human B lymphocytes

doi:10.1074/jbc.M513315200

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Papers In Press, published online ahead of print April 27, 2006
J. Biol. Chem, 10.1074/jbc.M513315200
Submitted on December 14, 2005
Revised on April 21, 2006
Accepted on April 27, 2006

Nuclear localization in the biology of the CD40 receptor in normal and neoplastic human B lymphocytes

Yen-Chiu Lin-Lee, Lan V. Pham, Archito T. Tamayo, Lingchen Fu, Hai-Jun Zhou, Linda C. Yoshimura, Glen L. Decker, and Richard J. Ford

Hematopathology, UT MD Anderson Cancer Center, Houston, TX 77030

Corresponding Author: rford{at}mdanderson.org

CD40 is a TNF receptor superfamily (TNRSF-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-GFP fusion-protein entered B-cell nuclei. The CD40 protein contains a nuclear localization signal (NLS) sequence, that when mutated, blocks entry of CD40 into the nucleus through the classic karyopherins (Importins-a/ßpathway). 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. CD40, another TNF family member, involved in cell survival in the B cell linkage, like other nuclear growth factor receptors, 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.

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