Role of phosphatidylinositol 3-kinase in anti-IgM-and anti-IgD-induced apoptosis in B cell lymphomas

G. B. Carey, D. W. Scott*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Cross-linking of surface Ig receptors with anti IgM (anti-μ heavy chain, anti-μ), but not anti-IgD (anti-δ heavy chain, anti-δ), Abs leads to growth arrest and apoptosis in several extensively characterized B cell lymphomas. By poorly understood mechanisms, both Igs transiently stimulate c-Myc protein expression. However, ultimately, only anti-μ causes a severe loss in c-Myc and a large induction of p27Kip1 protein expression. Because phosphatidylinositol 3-kinase (PI3K) has been established as a major modulator of cellular growth and survival, we investigated its role in mediating anti-Ig-stimulated outcomes. Herein, we show that PI3K pathways regulate cell cycle progression and apoptosis in the ECH408 B cell lymphoma. Anti-μ and anti-δ driven c-Myc protein changes precisely follow their effects on the PI3K effector, p70S6K. Upstream of p70S6K, signaling through both Ig receptors depresses PI3K pathway phospholiplds below control with time, which is followed by p27Kip1 induction. Conversely, anti-δ, but not anti-μ stimulated PI3K-dependent phosphollpid return to control levels by 4-8 h. Abrogation of the PI3K pathway with specific inhibitors mimics anti-μ action, potentiates anti-μ-induced cell death and, importantly, converts anti-δ to a death signal. Transfection with active PI3K Kinase construct induces anti-μ resistance, whereas transfection with dominant negative PI3K augments anti-μ sensitivity. Our results show that prolonged disengagement of PI3K or down-regulation of its products by anti-μ (and not anti-δ) determines B cell fate.

Original languageEnglish
Pages (from-to)1618-1626
Number of pages9
JournalJournal of Immunology
Issue number3
StatePublished - 1 Feb 2001
Externally publishedYes


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