title: Foxp2 inhibits Nkx2.1-mediated transcription of SP-C via interactions with the Nkx2.1 homeodomain.
abstract: The transcription factor (TF) Foxp2 has been shown to partially repress surfactant protein C (SP-C) transcription, presumably through interaction of an independent repressor domain with a conserved Foxp2 consensus site in the SP-C promoter. We explored the role of interactions between Foxp2 and the homeodomain TF Nkx2.1 that may contribute to the marked reduction in SP-C expression accompanying phenotypic transition of alveolar epithelial type II (AT2) to type I (AT1) cells. Foxp2 dose-dependently inhibited Nkx2.1-mediated activation of SP-C in MLE-15 cells. While electrophoretic mobility shift assays and chromatin immunoprecipitations revealed an interaction between Foxp2 and the conserved consensus motif in the SP-C promoter, Nkx2.1-mediated activation of the 318-bp proximal SP-C promoter (which lacks a Foxp2 consensus) was attenuated by increasing amounts of Foxp2. Co-immunoprecipitation and mammalian two-hybrid assays confirmed a physical interaction between Nkx2.1 and Foxp2 mediated through the Nkx2.1 homeodomain. Formation of an Nkx2.1 complex with an SP-C oligonucleotide was inhibited dose-dependently by recombinant Foxp2. These findings demonstrate that direct interaction between Foxp2 and Nkx2.1 inhibits Nkx2.1 DNA-binding and transcriptional activity and suggest a mechanism for down-regulation of SP-C (and probably other AT2 cell genes) during transition of AT2 cells to an AT1 cell phenotype.
authors.affiliation: Will Rogers Institute Pulmonary Research Center, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Southern California, 2020 Zonal Avenue, Los Angeles, CA 90033, USA.
authors.forename: Beiyun
authors.initials: B
authors.lastname: Zhou
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhong
authors.forename: Parviz
authors.initials: P
authors.lastname: Minoo
authors.forename: Changgong
authors.initials: C
authors.lastname: Li
authors.forename: David K
authors.initials: DK
authors.lastname: Ann
authors.forename: Baruch
authors.initials: B
authors.lastname: Frenkel
authors.forename: Edward E
authors.initials: EE
authors.lastname: Morrisey
authors.forename: Edward D
authors.initials: ED
authors.lastname: Crandall
authors.forename: Zea
authors.initials: Z
authors.lastname: Borok
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011650:Pulmonary Alveoli / Q000166:cytology; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques
chemical_list: D051858:Forkhead Transcription Factors; C432918:Foxp2 protein, mouse; C000614414:Nkx2-1 protein, mouse; C000614416:Nkx2-1 protein, rat; D009687:Nuclear Proteins; D037721:Pulmonary Surfactant-Associated Protein C; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors