The BCL2A1 gene as a pre-T cell receptor-induced regulator of thymocyte survival.
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.
Mandal
Malay
M
Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, IL 60637, USA.
Borowski
Christine
C
Palomero
Teresa
T
Ferrando
Adolfo A
AA
Oberdoerffer
Philipp
P
Meng
Fanyong
F
Ruiz-Vela
Antonio
A
Ciofani
Maria
M
Zuniga-Pflucker
Juan-Carlos
JC
Screpanti
Isabella
I
Look
A Thomas
AT
Korsmeyer
Stanley J
SJ
Rajewsky
Klaus
K
von Boehmer
Harald
H
Aifantis
Iannis
I
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D061945:Caspase Inhibitors; D002460:Cell Line; D002470:Cell Survival; D005786:Gene Expression Regulation; D019254:Genes, bcl-2 / Q000502:physiology*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000209:etiology / Q000378:metabolism; D008562:Membrane Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D010738:Type C Phospholipases / Q000378:metabolism
C096816:BCL2-related protein A1; D061945:Caspase Inhibitors; D008562:Membrane Glycoproteins; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; C090377:pre-T cell receptor alpha; D011493:Protein Kinase C; D010738:Type C Phospholipases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3
EMBO J. 2000 Mar 1;19(5):931-41
10698935
Nat Cell Biol. 2003 Sep;5(9):834-9
12942087
Mol Cell Biol. 2000 Apr;20(8):2687-95
10733571
Nature. 2000 Mar 23;404(6776):402-7
10746729
Cell. 1993 Oct 22;75(2):229-40
8402909
Cell. 1993 Oct 22;75(2):283-94
8402912
Nature. 1994 Mar 31;368(6470):457-60
8133891
Science. 1995 Mar 10;267(5203):1506-10
7878471
Immunity. 1996 Apr;4(4):387-96
8612133
Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9545-52
8790367
Biochem J. 2003 Dec 15;376(Pt 3):545-52
14570590
Nature. 2003 Dec 11;426(6967):671-6
14668867
Cancer Cell. 2003 Dec;4(6):451-61
14706337
J Exp Med. 2004 Mar 1;199(5):607-15
14993248
J Immunol. 2004 May 1;172(9):5230-9
15100261
J Immunol. 1993 May 15;150(10):4244-52
8387091
Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11400-6
8876147
Nature. 1997 Apr 17;386(6626):728-31
9109491
Cell. 1997 Jun 27;89(7):1011-9
9215624
Int Immunol. 1997 Sep;9(9):1291-301
9310832
Int Immunol. 1997 Sep;9(9):1375-84
9310841
Int Immunol. 1998 May;10(5):631-7
9645611
Oncogene. 1998 Jun 18;16(24):3105-14
9671389
Trends Cell Biol. 1998 Mar;8(3):107-11
9695819
Genes Dev. 1999 Feb 15;13(4):382-7
10049353
Curr Opin Immunol. 1999 Apr;11(2):135-42
10322152
Immunity. 1999 Jul;11(1):91-101
10435582
J Biol Chem. 2000 Jun 16;275(24):18099-107
10849436
EMBO J. 2000 Jul 3;19(13):3337-48
10880446
Immunity. 2000 Nov;13(5):677-89
11114380
Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):609-14
11149941
Blood. 2001 May 1;97(9):2798-807
11313274
Nat Immunol. 2001 May;2(5):403-9
11323693
J Exp Med. 2001 Jul 2;194(1):99-106
11435476
Mol Cell. 2001 Sep;8(3):705-11
11583631
Blood. 2001 Nov 15;98(10):3050-7
11698290
Nat Immunol. 2002 Mar;3(3):221-7
11875461
Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3788-93
11891328
Nat Immunol. 2002 May;3(5):483-8
11927911
Cancer Cell. 2002 Feb;1(1):75-87
12086890
Cancer Cell. 2002 Mar;1(2):133-43
12086872
J Biol Chem. 2002 Oct 18;277(42):39156-62
12114514
Immunity. 2002 Dec;17(6):749-56
12479821
Blood. 2003 Apr 1;101(7):2679-85
12406903
Mol Cell Biol. 2003 Apr;23(8):2749-61
12665576
Immunity. 2003 Jul;19(1):83-94
12871641
Cell Immunol. 2000 Feb 25;200(1):56-62
10716883