E2A proteins enforce a proliferation checkpoint in developing thymocytes.
E2A proteins regulate multiple stages of thymocyte development and suppress T-cell lymphoma. The activity of E2A proteins throughout thymocyte development is modulated by signals emanating from the pre-TCR and TCR. Here we demonstrate that E2A is required for the complete arrest in both differentiation and proliferation observed in thymocytes with defects in proteins that mediate pre-TCR signaling, including LAT, Lck and Fyn. We show that E2A proteins are required to prevent the accumulation of TCRbeta negative cells beyond the pre-TCR checkpoint. E2A-deficient thymocytes also exhibit abnormal cell-cycle progression prior to pre-TCR expression. Furthermore, we demonstrate that E47 can act in concert with Bcl-2 to induce cell-cycle arrest in vitro. These observations indicate that E2A proteins function during early thymocyte development to block cell-cycle progression prior to the expression of TCRbeta. In addition, these data provide further insight into how deficiencies in E2A lead to T lymphoma.
Engel
Isaac
I
Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.
Murre
Cornelis
C
D000818:Animals; D016827:CD8 Antigens / Q000378:metabolism; D002453:Cell Cycle; D002454:Cell Differentiation; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D018507:Gene Expression Regulation, Developmental; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D005801:Genes, Homeobox; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006720:Homozygote; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D051820:TCF Transcription Factors; D013950:Thymus Gland / Q000166:cytology* / Q000196:embryology; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors / Q000378:metabolism
D016827:CD8 Antigens; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D051820:TCF Transcription Factors; C544913:Tcf7l1 protein, mouse; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors