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Foxp2 Inhibits Nkx2.1-Mediated Transcription of SP-C via Interactions with the Nkx2.1 Homeodomain

¹ Will Rogers Institute Pulmonary Research Center, Division of Pulmonary and Critical Care Medicine, Department of Medicine, ² Department of Pharmacology and Pharmaceutical Sciences, ³ Department of Pediatrics, and ⁴ Department of Orthopedic Surgery, University of Southern California, Los Angeles, California; ⁵ Department of Clinical and Molecular Pharmacology, City of Hope Medical Center, Duarte, California; and ⁶ Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Correspondence and requests for reprints should be addressed to Zea Borok, M.D., Division of Pulmonary and Critical Care Medicine, University of Southern California, IRD 620, 2020 Zonal Avenue, Los Angeles, CA 90033. E-mail: zborok{at}usc.edu

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.

Key Words: alveolar epithelium • transcriptional regulation • forkhead box • Nkx2.1 • differentiation

CLINICAL RELEVANCE The research provides insight into transcriptional mechanisms that regulate transitions between alveolar epithelial type II and type I cells during normal maintenance of the epithelium and repair after injury.