Regulation of lymphocyte progenitor survival by the proapoptotic activities of Bim and Bid

Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20840-5. doi: 10.1073/pnas.0807557106. Epub 2008 Dec 16.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / genetics
  • Active Transport, Cell Nucleus / immunology
  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / immunology*
  • BH3 Interacting Domain Death Agonist Protein / genetics
  • BH3 Interacting Domain Death Agonist Protein / immunology*
  • Bcl-2-Like Protein 11
  • Cell Death / genetics
  • Cell Death / immunology
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cell Nucleus / genetics
  • Cell Nucleus / immunology
  • Cell Proliferation
  • Cell Survival / genetics
  • Cell Survival / immunology
  • DNA Damage / genetics
  • DNA Damage / immunology
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • Gene Rearrangement, T-Lymphocyte / genetics
  • Gene Rearrangement, T-Lymphocyte / immunology
  • Lymphoid Progenitor Cells / immunology*
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Mice
  • Mice, Knockout
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / immunology*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / immunology
  • Quantitative Trait Loci / genetics
  • Quantitative Trait Loci / immunology
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / immunology

Substances

  • Apoptosis Regulatory Proteins
  • BH3 Interacting Domain Death Agonist Protein
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Bid protein, mouse
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • FoxO3 protein, mouse
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Receptors, Antigen, T-Cell
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-akt