The ectodermal dysplasia receptor represses the Lef-1/beta-catenin-dependent transcription independent of NF-kappaB activation.
EDAR plays a key role in the process of ectodermal differentiation via activation of the NF-kappaB pathway. We present evidence that EDAR also represses Lef-1/beta-catenin-dependent transcription and this ability is defective in EDAR mutants associated with anhidrotic ectodermal dysplasia. While IKK1/IKKalpha and IKK2/IKKbeta are required for EDAR-induced NF-kappaB activation, they are dispensable for its ability to repress Lef-1/beta-catenin-dependent transcription. In contrast, NIK is not involved in EDAR-induced NF-kappaB activation or Lef-1/beta-catenin transcriptional repression. As Lef-1/beta-catenin pathway controls the expression of EDAR ligand, ectodysplasin-A (EDA), our results point to a negative feedback regulation of EDA-EDAR axis.
Shindo
Masahisa
M
The Hamon Center for Therapeutic Oncology Research and Division of Hematology-Oncology, UT Southwestern Medical Center, Dallas, TX 75390-8593, USA.
Chaudhary
Preet M
PM
D000818:Animals; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D004476:Ectodermal Dysplasia / Q000235:genetics / Q000378:metabolism*; D053339:Edar Receptor; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D051550:I-kappa B Kinase; D008156:Luciferases / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D053338:Receptors, Ectodysplasin; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*; D014162:Transfection; D051176:beta Catenin; D000097782:NF-kappaB-Inducing Kinase
D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D053339:Edar Receptor; D051550:I-kappa B Kinase; D008156:Luciferases; D051821:Lymphoid Enhancer-Binding Factor 1; D008565:Membrane Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D053338:Receptors, Ectodysplasin; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; D000097782:NF-kappaB-Inducing Kinase; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C506008:EDAR protein, human; C506009:Edar protein, mouse; C497573:LEF1 protein, human; C497574:Lef1 protein, mouse; C496559:CHUK protein, human; C496564:Chuk protein, mouse; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse