title: Conditional deletion of Pten causes bronchiolar hyperplasia.
abstract: Tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a lipid phosphatase that regulates multiple cellular processes including cell polarity, migration, proliferation, and carcinogenesis. In this work, we demonstrate that conditional deletion of Pten (Pten(Delta/Delta)) in the respiratory epithelial cells of the developing mouse lung caused epithelial cell proliferation and hyperplasia as early as 4 to 6 weeks of age. While bronchiolar cell differentiation was normal, as indicated by beta-tubulin and FOXJ1 expression in ciliated cells and by CCSP expression in nonciliated cells, cell proliferation (detected by expression of Ki-67, phospho-histone-H3, and cyclin D1) was increased and associated with activation of the AKT/mTOR survival pathway. Deletion of Pten caused papillary epithelial hyperplasia characterized by a hypercellular epithelium lining papillae with fibrovascular cores that protruded into the airway lumens. Cell polarity, as assessed by subcellular localization of cadherin, beta-catenin, and zonula occludens-1, was unaltered. PTEN is required for regulation of epithelial cell proliferation in the lung and for the maintenance of the normal simple columnar epithelium characteristics of bronchi and bronchioles.
authors.affiliation: Division of Pulmonary Biology, 4403, Cincinnati Children's Hospital Research Foundation, University of Cincinnati Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. davev0@cchmc.org
authors.forename: Vrushank
authors.initials: V
authors.lastname: Davé
authors.forename: Susan E
authors.initials: SE
authors.lastname: Wert
authors.forename: Tiffany
authors.initials: T
authors.lastname: Tanner
authors.forename: Angela R
authors.initials: AR
authors.lastname: Thitoff
authors.forename: Dave E
authors.initials: DE
authors.lastname: Loudy
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
mesh_terms: D000483:Alleles; D000818:Animals; D001980:Bronchi / Q000473:pathology*; D015740:Calcitonin Gene-Related Peptide / Q000032:analysis / Q000378:metabolism; D003433:Crosses, Genetic; D056741:Cyclin D; D016213:Cyclins / Q000032:analysis / Q000378:metabolism; D004318:Doxycycline / Q000008:administration & dosage; D017353:Gene Deletion; D006965:Hyperplasia / Q000209:etiology; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020545:Respiratory Mucosa / Q000196:embryology / Q000473:pathology
chemical_list: D056741:Cyclin D; D016213:Cyclins; D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D015740:Calcitonin Gene-Related Peptide; D004318:Doxycycline