p16 Regulation of Lung Epithelial Cell Growth, Repair after Injury and Transformation

Bibliographic Details
Main Author:	Sen, Moen
Language:	English
Published:	University of Cincinnati / OhioLINK 2017
Subjects:	Molecular Biology p16 transformation DNA damage RB1 lung injury
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504873926115934

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spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-ucin15048739261159342021-08-03T07:04:08Z p16 Regulation of Lung Epithelial Cell Growth, Repair after Injury and Transformation Sen, Moen Molecular Biology p16 transformation DNA damage RB1 lung injury p16, a critical regulator of cellular proliferation and senescence, is deregulated in the majority of adult malignancies. Inactivation of p16, most commonly by promoter methylation, is an early event in the pathogenesis of lung cancer and is observed in the bronchial epithelium of smokers before the advent of histological features of carcinogenesis. This suggests that p16 functions to regulate epithelial repair and suppress cancer initiation in response to injury induced by smoking. The most well established p16 function is in suppression of cell cycle progression through regulation of the G1/S checkpoint. The classic paradigm is that p16 exerts its cell cycle regulatory functions through activation of the downstream effector Retinoblastoma (RB1). However, unlike p16, RB1 loss is frequently observed in only one adult tumor, small cell lung cancer (SCLC). Despite its well established characterization as a tumor suppressor, there is minimal knowledge about how p16 functions to block transformation. The studies in this dissertation were thus designed to investigate the role of p16 in regulation of lung epithelial cell growth and transformation in the context of lung injury and oncogenic stress caused by RB1 deficiency. We demonstrate that p16 is induced in RB1 deficient lung epithelial cells in vivo. Despite p16 induction, RB1 deficient cells do not undergo senescence. Instead, p16 promotes the survival of RB1 deficient cells and protects them against DNA damage. Additional p16 loss resulted in increased propensity to immortalization and subsequent transformation of RB1 deficient cells and increased incidence of tumors with aggressive metastases in vivo. To investigate the role of p16 in the context of DNA damage in the lung in vivo, p16 proficient and deficient mice were treated with bleomycin. p16 loss resulted in a significant increase in lung injury with aberrant epithelial repair characterized by abnormal localization of proximal bronchiolar epithelial cells lining distal alveoli, similar to pathology seen in chronic lung diseases including idiopathic pulmonary fibrosis. In addition, p16 loss resulted in decreased survival after lung injury. These studies identify novel p16 functions in the lung epithelium critical for protection from oncogenic stress and lung injury and demonstrate that p16 is functionally active in the absence of RB1. Taken together, these findings increase our knowledge of p16 function in the pathogenesis of lung diseases and provide valuable model systems for future research. 2017 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504873926115934 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504873926115934 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection	NDLTD
language	English
sources	NDLTD
topic	Molecular Biology p16 transformation DNA damage RB1 lung injury
spellingShingle	Molecular Biology p16 transformation DNA damage RB1 lung injury Sen, Moen p16 Regulation of Lung Epithelial Cell Growth, Repair after Injury and Transformation
author	Sen, Moen
author_facet	Sen, Moen
author_sort	Sen, Moen
title	p16 Regulation of Lung Epithelial Cell Growth, Repair after Injury and Transformation
title_short	p16 Regulation of Lung Epithelial Cell Growth, Repair after Injury and Transformation
title_full	p16 Regulation of Lung Epithelial Cell Growth, Repair after Injury and Transformation
title_fullStr	p16 Regulation of Lung Epithelial Cell Growth, Repair after Injury and Transformation
title_full_unstemmed	p16 Regulation of Lung Epithelial Cell Growth, Repair after Injury and Transformation
title_sort	p16 regulation of lung epithelial cell growth, repair after injury and transformation
publisher	University of Cincinnati / OhioLINK
publishDate	2017
url	http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504873926115934
work_keys_str_mv	AT senmoen p16regulationoflungepithelialcellgrowthrepairafterinjuryandtransformation
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p16 Regulation of Lung Epithelial Cell Growth, Repair after Injury and Transformation

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