Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis
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Caspase 3
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Caspase Inhibitors
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Cell Line
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Cell Survival
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Gene Expression Regulation
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Genes, bcl-2 / physiology*
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Humans
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Leukemia-Lymphoma, Adult T-Cell / etiology
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Leukemia-Lymphoma, Adult T-Cell / metabolism
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Membrane Glycoproteins
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Mice
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Mice, Inbred C57BL
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Minor Histocompatibility Antigens
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NF-kappa B / metabolism
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Protein Kinase C / metabolism
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Proto-Oncogene Proteins c-bcl-2 / genetics*
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Receptors, Antigen, T-Cell / metabolism*
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Receptors, Antigen, T-Cell, alpha-beta
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Signal Transduction
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T-Lymphocytes / metabolism
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T-Lymphocytes / physiology*
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Type C Phospholipases / metabolism
Substances
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BCL2-related protein A1
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Caspase Inhibitors
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Membrane Glycoproteins
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Minor Histocompatibility Antigens
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NF-kappa B
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Antigen, T-Cell
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Receptors, Antigen, T-Cell, alpha-beta
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pre-T cell receptor alpha
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Protein Kinase C
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Type C Phospholipases
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CASP3 protein, human
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Casp3 protein, mouse
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Caspase 3