title: Miz-1 is required to coordinate the expression of TCRbeta and p53 effector genes at the pre-TCR "beta-selection" checkpoint.
abstract: Miz-1 is a Broad-complex, Tramtrack and Bric-à-brac/pox virus zinc finger domain (BTB/POZ)-containing protein expressed in lymphoid precursors that can activate or repress transcription. We report in this article that mice expressing a nonfunctional Miz-1 protein lacking the BTB/POZ domain (Miz-1(ΔPOZ)) have a severe differentiation block at the pre-T cell "β-selection" checkpoint, evident by a drastic reduction of CD4(-)CD8(-) double-negative-3 (DN3) and DN4 cell numbers. T cell-specific genes including Rag-1, Rag-2, CD3ε, pTα, and TCRβ are expressed in Miz-1-deficient cells and V(D)J recombination is intact, but few DN3/DN4 cells express a surface pre-TCR. Miz-1-deficient DN3 cells are highly apoptotic and do not divide, which is consistent with enhanced expression of p53 target genes such as Cdkn1a, PUMA, and Noxa. However, neither coexpression of the antiapoptotic protein Bcl2 nor the deletion of p21(CIP1) nor the combination of both relieved Miz-1-deficient DN3/DN4 cells from their differentiation block. Only the coexpression of rearranged TCRαβ and Bcl2 fully rescued Miz-1-deficient DN3/DN4 cell numbers and enabled them to differentiate into DN4TCRβ(+) and double-positive cells. We propose that Miz-1 is a critical factor for the β-selection checkpoint and is required for both the regulation of p53 target genes and proper expression of the pre-TCR to support the proliferative burst of DN3 cells during T cell development.
authors.affiliation: Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Saba
authors.forename: Christian
authors.initials: C
authors.lastname: Kosan
authors.forename: Lothar
authors.initials: L
authors.lastname: Vassen
authors.forename: Ludger
authors.initials: L
authors.lastname: Klein-Hitpass
authors.forename: Tarik
authors.initials: T
authors.lastname: Möröy
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology*; D019674:Genes, T-Cell Receptor beta; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics; D044767:Ubiquitin-Protein Ligases
chemical_list: D009687:Nuclear Proteins; D050828:Protein Inhibitors of Activated STAT; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016159:Tumor Suppressor Protein p53; C485521:Miz1 protein, mouse; D044767:Ubiquitin-Protein Ligases