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Mandal, M, Borowski, C, Palomero, T, Ferrando, AA, Oberdoerffer, P, Meng, F, Ruiz-Vela, A, Ciofani, M, Zuniga-Pflucker, JC, Screpanti, I, Look, AT, Korsmeyer, SJ, Rajewsky, K, von Boehmer, H and Aifantis, I (2005) The BCL2A1 gene as a pre-T cell receptor-induced regulator of thymocyte survival. J. Exp. Med. 201:603-14
The pre-T cell receptor (TCR) is expressed early during T cell development and imposes a tight selection for differentiating T cell progenitors. Pre-TCR-expressing cells are selected to survive and differentiate further, whereas pre-TCR(-) cells are "negatively" selected to die. The mechanisms of pre-TCR-mediated survival are poorly understood. Here, we describe the induction of the antiapoptotic gene BCL2A1 (A1) as a potential mechanism regulating inhibition of pre-T cell death. We characterize in detail the signaling pathway involved in A1 induction and show that A1 expression can induce pre-T cell survival by inhibiting activation of caspase-3. Moreover, we show that in vitro "knockdown" of A1 expression can compromise survival even in the presence of a functional pre-TCR. Finally, we suggest that pre-TCR-induced A1 overexpression can contribute to T cell leukemia in both mice and humans.
Animals; Apoptosis; Caspase 3; Caspases/antagonists & inhibitors; Cell Line; Cell Survival; Gene Expression Regulation; Genes, bcl-2/physiology; Humans; Leukemia-Lymphoma, Adult T-Cell/etiology; Leukemia-Lymphoma, Adult T-Cell/metabolism; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; NF-kappa B/metabolism; Protein Kinase C/metabolism; Proto-Oncogene Proteins c-bcl-2/biosynthesis; Proto-Oncogene Proteins c-bcl-2/genetics; Receptors, Antigen, T-Cell/metabolism; Receptors, Antigen, T-Cell, alpha-beta; Signal Transduction; T-Lymphocytes/metabolism; T-Lymphocytes/physiology; Type C Phospholipases/metabolism
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