title: T-cells null for the MED23 subunit of mediator express decreased levels of KLF2 and inefficiently populate the peripheral lymphoid organs.
abstract: MED23, a subunit of the Mediator coactivator complex, is important for the expression of a subset of MAPK/ERK pathway-responsive genes, the constituents of which vary between cell types for reasons that are not completely clear. MAPK/ERK pathway-dependent processes are essential for T-cell development and function, but whether MED23 has a role in this context is unknown. We generated Med23 conditional knockout mice and induced Med23 deletion in early T-cell development using the lineage specific Lck-Cre transgene. While the total cell number and distribution of cell populations in the thymuses of Med23flox/flox;Lck-Cre mice were essentially normal, MED23 null T-cells failed to efficiently populate the peripheral lymphoid organs. MED23 null thymocytes displayed decreased expression of the MAPK/ERK-responsive genes Egr1, Egr2, as well as of the membrane glycoprotein Cd52 (CAMPATH-1). MED23 null CD4 single-positive thymocytes also showed decreased expression of KLF2 (LKLF), a T-cell master regulatory transcription factor. Indeed, similarities between the phenotypes of mice lacking MED23 or KLF2 in T-cells suggest that KLF2 deficiency in MED23 null T-cells is one of their key defects. Mechanistic experiments using MED23 null MEFs further suggest that MED23 is required for full activity of the MAPK-responsive transcription factor MEF2, which has previously been shown to mediate Klf2 expression. In summary, our data indicate that MED23 has critical roles in enabling T-cells to populate the peripheral lymphoid organs, possibly by potentiating MEF2-dependent expression of the T-cell transcription factor KLF2.
authors: Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Lawryn H
authors: LH
authors: Kasper
authors: Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Tomofusa
authors: T
authors: Fukuyama
authors: Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors: Paul K
authors: PK
authors: Brindle
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008221:Lymphoid Tissue / Q000166:cytology / Q000378:metabolism*; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D056892:Mediator Complex / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism*; D060168:Thymocytes / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism
chemical_list: C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D064326:MEF2 Transcription Factors; C541034:Med23 protein, mouse; D056892:Mediator Complex