Conditional deletion of Pten causes bronchiolar hyperplasia.
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.
Davé
Vrushank
V
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
Wert
Susan E
SE
Tanner
Tiffany
T
Thitoff
Angela R
AR
Loudy
Dave E
DE
Whitsett
Jeffrey A
JA
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
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