c-Src tyrosine kinase co-associates with and phosphorylates signal transducer and activator of transcription 5b which mediates the proliferation of normal human B lymphocytes

Cayer, Marie-Pierre; Proulx, Maryse; Ma, Xiongfeng; Sakac, Darinka; Giguère, Jean-François; Drouin, Mathieu; Néron, Sonia; Branch, Donald R.; Jung, Daniel

doi:10.1111/j.1365-2249.2009.03917.x

Cited by 8 publications

(4 citation statements)

References 38 publications

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“…2a, following EYFP-Ad5/F35 transduction, the viability of RPMI and U266 cells starts to decline on day 3 after transduction, reaching a viability of 75-80% at 6-7 days post-infection. These results are consistent with our previous observations that Ad5/F35 exerts a negative impact on lymphoid cell viability [27]. Similarly, PAX5-Ad5/F35 induces a decrease in viability after transduction of RPMI and U266 cells (Fig.…”

Section: Pax5 Overexpression Influences Plasma Cell Viabilitysupporting

confidence: 93%

Overexpression of PAX5 induces apoptosis in multiple myeloma cells

et al. 2010

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PAX5 is an essential transcription factor for the commitment of lymphoid progenitors to the B-lymphocyte lineage. PAX5 suppression results in retrodifferentiation of B lymphocytes to an uncommitted progenitor cell stage, whereas PAX5 suppression in mature B lymphocytes leads to further development into plasma cells. Here, we have analyzed the fate of plasma cell lines following PAX5 reexpression. Human B cell lines were infected with Ad5/F35 adenoviruses encoding either EYFP or PAX5. Expression analysis of specific plasma cell transcription factors (IRF4, Blimp-1 and XBP-1) suggests that PAX5 reexpression does not induce retrodifferentiation of plasma cells into B lymphocytes. Interestingly, the viability of RPMI-8226 and U266 multiple myeloma cell lines markedly declined at 4-7 days post-transduction, whereas other plasma cell lines maintained their viability. Apoptosis analysis through Annexin V measurement also revealed a higher level of apoptosis in PAX5-expressing myeloma cell lines. Finally, Western blot analysis of pro- and anti-apoptotic proteins revealed that the anti-apoptotic protein MCL-1 was down-modulated in PAX5-transduced multiple myeloma cell lines. In conclusion, our results show that the expression of PAX5 in plasma cell lines induces apoptosis exclusively in multiple myelomas. This might represent a potential therapeutic avenue in the treatment of multiple myeloma.

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Section: Pax5 Overexpression Influences Plasma Cell Viabilitysupporting

confidence: 93%

Overexpression of PAX5 induces apoptosis in multiple myeloma cells

et al. 2010

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“…Binding of CD154 to CD40 can also trigger activation of Src protein tyrosine kinase, which appears to have a role in proliferation of normal and transformed B cells (Cayer et al 2009;Néron et al 2006). It has been reported that CD40-dependent protein kinase A activation regulates NF-jB-dependent promoter activity in human B cells (Lapointe et al 1996), and that CD40 could also activate phospholipase C gamma and protein tyrosine kinases (Lapointe et al 1996;Ren et al 1994).…”

Section: Signaling Through Cd40: An Overviewmentioning

confidence: 99%

Tuning of CD40–CD154 Interactions in Human B-Lymphocyte Activation: A Broad Array of In Vitro Models for a Complex In Vivo Situation

Néron

Nadeau

Darveau

et al. 2011

Arch. Immunol. Ther. Exp.

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Naive and memory B-lymphocyte populations can be activated through the binding of CD154 to CD40, a receptor that is constitutively expressed on the surface of these cells. Models based on the in vitro stimulation of human B lymphocytes through CD40 have greatly contributed to our understanding of the human immune response in healthy individuals and patients suffering from immune disorders. The nature of the engineered CD40 ligands is as diverse as the in vitro models used in studies of CD40-activated B lymphocytes. Monoclonal anti-CD40 antibodies, recombinant CD154 proteins, soluble CD154(+) membranes as well as CD154(+) cell lines have turned out to be very useful tools, and are still in use today. As for any receptor-ligand interaction, parameters such as duration and strength of contact, timing, affinity, and receptor density are major determinants of CD40 binding by CD154 or anti-CD40. Furthermore, variation in the intensity of CD40 stimulation has been shown to influence proliferation, differentiation and immunoglobulin secretion of human hybridomas, B-cell lines, tonsil and blood B lymphocytes. The objective of this review is to present an overview of the great diversity of CD40 agonists used in in vitro models of B-lymphocyte activation, with a particular emphasis on variations in the resulting strength of CD40 signaling generated by these models. A better understanding of these models could open up new avenues for the rational use of human B lymphocytes as antigen-presenting cells in cellular therapies.

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“…Recently, CD40L was shown to induce, in B cells, the expression and activation of c-Src tyrosine kinase that could associate with and phosphorylate STAT5a and STAT5b. [25][26][27] We thus hypothesized that the cooperation of CD40L and IL-15 for the induction of P-STAT5 could be mediated through c-Src. Indeed, PP2, a selective inhibitor of c-Src, completely abolished …”

Section: Il-15 and Cd40l Synergy In B Cells G Epron Et Almentioning

confidence: 99%

Monocytes and T cells cooperate to favor normal and follicular lymphoma B-cell growth: role of IL-15 and CD40L signaling

et al. 2011

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Interleukin-15 (IL-15) has been extensively studied for its role in the survival and proliferation of NK and T cells through a unique mechanism of trans-presentation by producer cells. Conversely, whereas activated B cells have been described as IL-15-responding cells, the cellular and molecular context sustaining this effect remains unexplored. In this study, we found that, whereas human B cells could not respond to soluble IL-15, monocytes and lymphoid tissue-derived macrophages but not stromal cells efficiently trans-present IL-15 to normal B cells and cooperate with T-cell-derived CD40L to promote IL-15-dependent B-cell proliferation. Furthermore, CD40L signaling triggers a Src-independent upregulation of STAT5 expression and favors a Src-dependent phosphorylation of STAT5 in response to IL-15. In follicular lymphoma (FL), immunohistochemical studies reported a strong relationship between malignant B cells, infiltrating macrophages and T cells. We show here an overexpression of IL-15 in purified tumor-associated macrophages, and STAT5A in purified tumor B cells. Moreover, FL B cells respond to IL-15 trans-presented by monocytes/macrophages, in particular, in the presence of CD40L-mediated signaling. This cooperation between IL-15 and CD40L reinforces the importance of tumor microenvironment and unravels a mechanism of FL growth that should be considered if using IL-15 as a drug in this disease.

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c-Src tyrosine kinase co-associates with and phosphorylates signal transducer and activator of transcription 5b which mediates the proliferation of normal human B lymphocytes

Cited by 8 publications

References 38 publications

Overexpression of PAX5 induces apoptosis in multiple myeloma cells

Overexpression of PAX5 induces apoptosis in multiple myeloma cells

Tuning of CD40–CD154 Interactions in Human B-Lymphocyte Activation: A Broad Array of In Vitro Models for a Complex In Vivo Situation

Monocytes and T cells cooperate to favor normal and follicular lymphoma B-cell growth: role of IL-15 and CD40L signaling

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