Research Article: A Role for Bcl-2 in Notch1-Dependent Transcription in Thymic Lymphoma Cells

Date Published: January 26, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Ronit Vogt Sionov, Shlomit Kfir-Erenfeld, Rachel Spokoini, Eitan Yefenof.


Notch1 is a transcription factor important for T-cell development. Notch1 is active in double negative (DN) thymocytes, while being depressed in double positive (DP) thymocytes. Synchronously, the expression of Bcl-2 becomes downregulated during the transition from DN to DP thymocytes. We previously observed that overexpression of an intracellular active Notch1 (ICN) in Bcl-2-positive 2B4 T cells leads to the transcription of Notch1-regulated genes. However, these genes were not induced in Bcl-2-negative DP PD1.6 thymic lymphoma cells overexpressing ICN. Here we show that, when Bcl-2 is simultaneously introduced into these cells, Notch-regulated genes are transcribed. Only in the presence of both Bcl-2 and ICN, PD1.6 thymic lymphoma cells become resistant to glucocorticoid (GC)-induced apoptosis. Our data suggest that Bcl-2 plays a role in modulating Notch1 function in T cells.

Partial Text

Notch1 signaling plays a critical role in promoting cell growth, proliferation, and survival of immature T cells [1]. In the thymus, Notch signals are critical throughout the double negative (DN) stages for the maintenance of T-cell specification and for continued differentiation of αβ T cells past the β-selection checkpoint [2]. Upon interaction with its ligands (e.g., Delta-like 1, Delta-like 4, Jagged 1, and Jagged 2), the Notch1 protein undergoes two proteolytic events, leading to the release of the intracellular Notch domain (ICN). Subsequently, ICN translocates to the nucleus and activates transcription of target genes through its association with C-promoter binding factor 1-recombination binding protein Jκ (CBF1-RBPJκ) and various members of the Mastermind family [2].

In this paper we provide evidence that Bcl-2 affects Notch1 function in immature thymic lymphocytes. In DP thymic cells, Notch1 is unable to induce its target genes Deltex1 and Hes1 in the absence of Bcl-2. When Bcl-2 is coexpressed, Notch1 transcriptional function is activated. This is accompanied by the acquisition of GC resistance. This concords with findings showing that both Deltex1 and Hes1 contribute to GC resistance [21, 22]. Another appreciated antiapoptotic function of Notch is linked to the activation of the PI3K-Akt pathway [19]. While in ICN-overexpressing 2B4 cells Akt is activated [7, 8], there is no indication for Akt activation in PD1.6Bcl-2Notch1 cells. The reason for the inability of Notch1 to activate Akt in these cells is not known, but could be related to high Csk activity (unpublished data). Thus, another mechanism is likely to be responsible for Notch1-induced GC resistance. A protrusive feature of PD1.6Bcl-2Notch1 cells is the reduction in both GR expression and GR Ser211 phosphorylation. The reduced GR expression may be related to the elevated Hes1 expression in these cells. Hes1 has been shown to downregulate GR expression in acute T lymphoblastic leukemia [21]. Since sufficient GR expression level is required for GC-induced apoptosis [13], the reduction in GR expression and Ser211 phosphorylation by Notch-1 overexpression is likely to contribute to GC resistance.




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