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Conditional Deletion of Pten Causes Bronchiolar Hyperplasia

¹ Division of Pulmonary, Neonatology, and Perinatal Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio

Correspondence and requests for reprints should be addressed to Vrushank Davé, Ph.D., Division of Pulmonary Biology, 4403, Cincinnati Children's Hospital Research Foundation, University of Cincinnati Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229. E-mail: davev0{at}cchmc.org

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^/) 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 β-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, β-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.

Key Words: PTEN • AKT • bronchiolar • hyperplasia • cell-cycle

CLINICAL RELEVANCE Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) regulates epithelial cell proliferation and maintenance of epithelial cellularity in the conducting airways. PTEN may modulate dynamic changes in the conducting epithelial cells as observed in cystic fibrosis, chronic obstructive pulmonary disease, asthma, and idiopathic pulmonary fibrosis.