c-Myb regulates the proliferation of immature thymocytes following beta-selection.
Transgenic mice expressing a T-cell-specific dominant interfering allele (MEnT) of the c-Myb transcription factor have a pronounced block in CD4(-)CD8(-) (DN) development. In this study we show that differentiation of DN MEnT thymocytes is blocked due to the failure of cells to enter the cell cycle following beta-selection, the process by which productive rearrangement of the T-cell receptor (TCR) beta-chain permits maturation of cells into CD4(+)CD8(+) (DP) thymocytes. c-myb mRNA continues to be expressed in DN cells in mice lacking a functional pre-TCR signalling pathway, implying that its transcriptional regulation is independent of the signalling events regulating beta-selection. It is also expressed in the absence of cytokine signalling. However, we show that c-Myb protein is required for the function in beta-selection of its known upstream activator, the serine/threonine kinase Pim1: MEnT expression inhibits the cell cycle in Pim1 transgenic DN thymocytes and prevents Pim1-mediated rescue of a RAG1(-/-) developmental block. Super activation of c-Myb by Pim1 may therefore be required for beta-selection.
Pearson
R
R
CRC Centre for Cell and Molecular Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
Weston
K
K
D000483:Alleles; D000818:Animals; D001483:Base Sequence; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D002453:Cell Cycle; D002454:Cell Differentiation; D002455:Cell Division; D017931:DNA Primers / Q000235:genetics; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D020570:Genes, myb; D006410:Hematopoiesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism*; D051573:Proto-Oncogene Proteins c-pim-1; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*
D015704:CD4 Antigens; D016827:CD8 Antigens; D017931:DNA Primers; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; C496636:Pim1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1