BAFF-R promotes cell proliferation and survival through interaction with IKKbeta and NF-kappaB/c-Rel in the nucleus of normal and neoplastic B-lymphoid cells

• Published in: Blood 2009-05, Vol.113 (19), p.4627
• Main Authors: Fu, Lingchen, Lin-Lee, Yen-Chiu, Pham, Lan V, Tamayo, Archito T, Yoshimura, Linda C, Ford, Richard J
• Format: Article
• Language: English
• Subjects: B-Cell Activation Factor Receptor - physiology; B-Lymphocytes - cytology; B-Lymphocytes - metabolism; Blotting, Western; Cell Nucleus - metabolism; Cell Proliferation; Cell Survival - physiology; Cells, Cultured; Chromatin Immunoprecipitation; Genes, rel; Histones - metabolism; Humans; I-kappa B Kinase - genetics; I-kappa B Kinase - metabolism; Lymphocytes - metabolism; Lymphoma, B-Cell - metabolism; Mutagenesis, Site-Directed; NF-kappa B - genetics; NF-kappa B - metabolism; Phosphorylation; Plasmids; Promoter Regions, Genetic; Proto-Oncogene Proteins c-rel - genetics; Proto-Oncogene Proteins c-rel - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Subcellular Fractions
• ISSN: 1528-0020
• DOI: 10.1182/blood-2008-10-183467

BLyS and its major receptor BAFF-R have been shown to be critical for development and homeostasis of normal B lymphocytes, and for cell growth and survival of neoplastic B lymphocytes, but the biologic mechanisms of this ligand/receptor-derived intracellular signaling pathway(s) have not been completely defined. We have discovered that the BAFF-R protein was present in the cell nucleus, in addition to its integral presence in the plasma membrane and cytoplasm, in both normal and neoplastic B cells. BAFF-R interacted with histone H3 and IKKbeta in the cell nucleus, enhancing histone H3 phosphorylation through IKKbeta. Nuclear BAFF-R was also associated with NF-kappaB/c-Rel and bound to NF-kappaB targeted promoters including BLyS, CD154, Bcl-xL, IL-8, and Bfl-1/A1, promoting the transcription of these genes. These observations suggested that in addition to activating NF-kappaB pathways in the plasma membrane, BAFF-R also promotes normal B-cell and B-cell non-Hodgkin lymphoma (NHL-B) survival and proliferation by functioning as a transcriptional regulator through a chromatin remodeling mechanism(s) and NF-kappaB association. Our studies provide an expanded conceptual view of the BAFF-R signaling, which should contribute a better understanding of the physiologic mechanisms involved in normal B-cell survival and growth, as well as in the pathophysiology of aggressive B-cell malignancies and autoimmune diseases.