Journal
BLOOD
Volume 113, Issue 19, Pages 4627-4636Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-10-183467
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Funding
- National Cancer Institute (Washington, DC) [CA-R01-100836]
- Cancer Center (Washington, DC) [CA-16672-26]
- Farahi Family Foundation
- Lymphoma Research Foundation of America
- Leukemia & Lymphoma Society [LSS 6087-08]
- Odyssey program
- Kimberly-Clark Foundation
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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 neoplasticB cells. BAFF-R interacted with histone H3 and IKK beta in the cell nucleus, enhancing histone H3 phosphorylation through IKK beta. Nuclear BAFF-R was also associated with NF-kappa B/c-Rel and bound to NF-kappa B 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-kappa B 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-kappa B 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. (Blood. 2009;113:4627-4636)
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