title: Ectopic expression of a small cell lung cancer transcription factor, INSM1 impairs alveologenesis in lung development.
abstract: BACKGROUND
  Insulinoma associated-1 (INSM1) gene is expressed exclusively in early embryonic neuroendocrine tissues, but has been found highly re-activated in most of the neuroendocrine tumors including small cell lung carcinoma.
  
  
  METHODS
  In order to elucidate the functional effects of INSM1 in normal lung development, we used a conditional lung-specific INSM1 transgenic mouse model. Transgenic (Tet-on system) CMV-INSM1 responder mice were bred with the lung-specific, club cell secretory protein (CCSP) promoter-rtTA activator mice to produce bi-transgenic progeny carrying both alleles, CCSP-rtTA and Tet-on-INSM1. Mice were fed with doxycycline containing food at the initial mating day to the postnatal day 21. Lung samples were collected at embryonic day 17.5, newborn, and postnatal day 21 for analyses.
  
  
  RESULTS
  Northern blot, RT-PCR, and immunohistochemical analyses revealed that doxycycline induced respiratory epithelium-specific INSM1 expression in bi-transgenic mice. Samples from postnatal day 21 mice revealed a larger lung size in the bi-transgenic mouse as compared to the single-transgenic or wild-type littermates. The histopathology results showed that the alveolar space in the bi-transgenic mice were 4 times larger than those in the single transgenic or wild-type littermates. In contrast, the size was not significantly different in the lungs collected at E17.5 or newborn among the bi-transgenic, single transgenic, or wild type mice. The respiratory epithelium with INSM1 ectopic expression suppressed cyclin D1 signal. Further in vitro studies revealed that the ectopic expression of INSM1 suppresses cyclin D1 expression and delays cell cycle progression.
  
  
  CONCLUSIONS
  The current study suggests that CCSP promoter-driven INSM1 ectopic expression impairs normal lung development especially in postnatal alveologenesis.
authors.affiliation: Research Institute for Children, Children's Hospital, 200 Henry Clay Avenue, Research and Education Building, Room. 2211, New Orleans, LA, 70118, USA.|Departments of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA.
authors.forename: Chiachen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Research Institute for Children, Children's Hospital, 200 Henry Clay Avenue, Research and Education Building, Room. 2211, New Orleans, LA, 70118, USA.|Departments of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA.
authors.forename: Mary B
authors.initials: MB
authors.lastname: Breslin
authors.affiliation: Research Institute for Children, Children's Hospital, 200 Henry Clay Avenue, Research and Education Building, Room. 2211, New Orleans, LA, 70118, USA. mlan@lsuhsc.edu.|Departments of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA. mlan@lsuhsc.edu.|Departments of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA. mlan@lsuhsc.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lan
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D019938:Cyclin D1 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D000066630:Ectopic Gene Expression / Q000235:genetics*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011650:Pulmonary Alveoli / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism; D012097:Repressor Proteins; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055752:Small Cell Lung Carcinoma / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C477059:Insm1 protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors; D019938:Cyclin D1
keywords: Alveologenesis; CCSP; Cyclin D1; INSM1; Lung development; SCLC; Transgenic model