Nuclear CD40 interacts with c-Rel and enhances proliferation in aggressive B-cell lymphoma.
CD40 is an integral plasma membrane-associated member of the TNF receptor family that has recently been shown to also reside in the nucleus of both normal B cells and large B-cell lymphoma (LBCL) cells. However, the physiological function of CD40 in the B-cell nucleus has not been examined. In this study, we demonstrate that nuclear CD40 interacts with the NF-kappaB protein c-Rel, but not p65, in LBCL cells. Nuclear CD40 forms complexes with c-Rel on the promoters of NF-kappaB target genes, CD154, BLyS/BAFF, and Bfl-1/A1, in various LBCL cell lines. Wild-type CD40, but not NLS-mutated CD40, further enhances c-Rel-mediated Blys promoter activation as well as proliferation in LBCL cells. Studies in normal B cells and LBCL patient cells further support a nuclear transcriptional function for CD40 and c-Rel. Cooperation between nuclear CD40 and c-Rel appears to be important in regulating cell growth and survival genes involved in lymphoma cell proliferation and survival mechanisms. Modulating the nuclear function of CD40 and c-Rel could reveal new mechanisms in LBCL pathophysiology and provide potential new targets for lymphoma therapy.
Zhou
Hai-Jun
HJ
Department of Hematopathology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Pham
Lan V
LV
Tamayo
Archito T
AT
Lin-Lee
Yen-Chiu
YC
Fu
Lingchen
L
Yoshimura
Linda C
LC
Ford
Richard J
RJ
D053264:B-Cell Activating Factor / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D020573:Genes, rel / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D013936:Thymidine / Q000378:metabolism; D014162:Transfection; D001616:beta-Galactosidase / Q000378:metabolism
D053264:B-Cell Activating Factor; D019013:CD40 Antigens; D008156:Luciferases; D001616:beta-Galactosidase; D013936:Thymidine