Regulation of lymphocyte progenitor survival by the proapoptotic activities of Bim and Bid.
On their entry into the thymus, developing lymphocyte progenitors depend on signaling from the pre-T cell receptor (pre-TCR), which orchestrates differentiation, cell proliferation, and survival. The exact mechanism of pre-TCR-mediated suppression of T cell death remains unclear and controversial. Here, we identify Bim and Bid, 2 members of the BH3-only group of the BCL2 family, as important regulators of pre-T cell death. Both factors are highly expressed in proapoptotic thymocytes and their expression is suppressed on signaling through the pre-TCR. Their expression is directly regulated by the transcription factors FoxO3a and p53. Bid expression and p53 activity are related to the ongoing rearrangement of the TCR loci and induced DNA damage responses. Bim expression and FoxO3a nuclear translocation are directly controlled by the pre-TCR by means of its downstream kinase Akt/PKB. Interestingly, deletion of either gene on a pre-TCR(-/-) background rescues survival, but fails to induce further progenitor differentiation uncoupling the 2 processes.
Mandal
Malay
M
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Crusio
Kelly M
KM
Meng
Fanyong
F
Liu
Suqing
S
Kinsella
Marcus
M
Clark
Marcus R
MR
Takeuchi
Osamu
O
Aifantis
Iannis
I
D021581:Active Transport, Cell Nucleus / Q000235:genetics / Q000276:immunology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000276:immunology*; D000072224:Bcl-2-Like Protein 11; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002467:Cell Nucleus / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D004249:DNA Damage / Q000235:genetics / Q000276:immunology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D015329:Gene Rearrangement, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D054503:Lymphoid Progenitor Cells / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D040641:Quantitative Trait Loci / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology
D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C494815:Bid protein, mouse; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt