%0 Journal Article
%T A Role for Bcl-2 in Notch1-Dependent Transcription in Thymic Lymphoma Cells
%A Ronit Vogt Sionov
%A Shlomit Kfir-Erenfeld
%A Rachel Spokoini
%A Eitan Yefenof
%J Advances in Hematology
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/435241
%X 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. 1. Introduction 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 ¦Á¦Â T cells past the ¦Â-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 J (CBF1-RBPJ ) and various members of the Mastermind family [2]. Notch signaling is active in DN, CD4+, and CD8+ single positive (SP) thymocytes, while being repressed in CD4+8+ double positive (DP) thymocytes [3, 4]. Similarly, DN, CD4+, and CD8+ SP thymocytes express elevated levels of Bcl-2, whereas DP thymocytes express low levels of Bcl-2 [5, 6]. Both Notch1 [3, 7, 8] and Bcl-2 [9¨C11] confer resistance to glucocorticoid (GC)-induced apoptosis. However, this resistance is partial as prolonged exposure to GCs leads to apoptosis of immature T cells overexpressing either Notch1 or Bcl-2 [8¨C10]. Bcl-2 is an antiapoptotic protein that regulates apoptosis along the intrinsic mitochondrial apoptosis pathway [12]. The alterations in Notch signaling and Bcl-2 expression during thymocyte development may explain the extreme susceptibility of DP thymocytes to GC-induced apoptosis, while DN and SP thymocytes are relatively resistant [13]. The 2B4 T hybridoma and
%U http://www.hindawi.com/journals/ah/2012/435241/