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Hippo-Foxa2 signaling pathway plays a role in peripheral lung maturation and surfactant homeostasis.
Chung, Chaeuk; Kim, Tackhoon; Kim, Miju; Kim, Minchul; Song, Hoogeun; Kim, Tae-Shin; Seo, Eunjeong; Lee, Sang-Hee; Kim, Hanbyul; Kim, Sang Kyum; Yoo, Geon; Lee, Da-Hye; Hwang, Deog-Su; Kinashi, Tatsuo; Kim, Jin-Man; Lim, Dae-Sik.
Afiliação
  • Chung C; Department of Biological Sciences, National Creative Research Initiatives Center, Biomedical Research Center, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
Proc Natl Acad Sci U S A ; 110(19): 7732-7, 2013 May 07.
Article em En | MEDLINE | ID: mdl-23620511
Respiratory distress syndrome (RDS), which is induced by insufficient production of surfactant, is the leading cause of mortality in preterm babies. Although several transcription factors are known to be involved in surfactant protein expression, the molecular mechanisms and signaling pathways upstream of these transcription factors have remained elusive. Here, using mammalian Hippo kinases (Mst1/2, mammalian sterile 20-like kinase 1/2) conditional knockout mice, we demonstrate that Mst1/2 kinases are critical for orchestration of transcription factors involved in surfactant protein homeostasis and prevention of RDS. Mice lacking Mst1/2 in the respiratory epithelium exhibited perinatal mortality with respiratory failure and their lungs contained fewer type I pneumocytes and more immature type II pneumocytes lacking microvilli, lamellar bodies, and surfactant protein expression, pointing to peripheral lung immaturity and RDS. In contrast to previous findings of YAP (Yes-associated protein)-mediated canonical Hippo signaling in the liver and intestine, loss of Mst1/2 kinases induced the defects in pneumocyte differentiation independently of YAP hyperactivity. We instead found that Mst1/2 kinases stabilized and phosphorylated the transcription factor Foxa2 (forkhead box A2), which regulates pneumocyte maturation and surfactant protein expression. Taken together, our results suggest that the mammalian Hippo kinases play crucial roles in surfactant homeostasis and coordination of peripheral lung differentiation through regulation of Foxa2 rather than of YAP.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Regulação da Expressão Gênica / Proteínas Serina-Treonina Quinases / Regulação da Expressão Gênica no Desenvolvimento / Proteínas Associadas a Surfactantes Pulmonares / Fator 3-beta Nuclear de Hepatócito Limite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2013 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Regulação da Expressão Gênica / Proteínas Serina-Treonina Quinases / Regulação da Expressão Gênica no Desenvolvimento / Proteínas Associadas a Surfactantes Pulmonares / Fator 3-beta Nuclear de Hepatócito Limite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2013 Tipo de documento: Article