DNA replication in progenitor cells and epithelial regeneration after lung injury requires the oncoprotein MDM2
| Autor: | Swati Palit Deb, Ross B. Mikkelsen, Christopher S. Rabender, Sumitra Deb, Catherine A. Vaughan, Shilpa Singh |
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| Rok vydání: | 2019 |
| Předmět: |
DNA Replication
0301 basic medicine Epithelial-Mesenchymal Transition Notch signaling pathway Naphthalenes Biology Lung injury Alveolar cells Mice 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Regeneration Gene Knock-In Techniques Epithelial–mesenchymal transition Progenitor cell Lung Cell Proliferation Mice Knockout Receptors Notch Stem Cells Regeneration (biology) DNA replication Epithelial Cells Proto-Oncogene Proteins c-mdm2 Lung Injury General Medicine respiratory system Cell biology Disease Models Animal 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Tumor Suppressor Protein p53 Proto-Oncogene Proteins c-akt DNA Damage Signal Transduction Research Article Adult stem cell |
| Zdroj: | JCI Insight. 4 |
| ISSN: | 2379-3708 |
| Popis: | Depletion of epithelial cells after lung injury prompts proliferation and epithelial mesenchymal transition (EMT) of progenitor cells, and this repopulates the lost epithelial layer. To investigate the cell proliferative function of human oncoprotein MDM2, we generated mouse models targeting human MDM2 expression in either lung Club or alveolar cells after doxycycline treatment. We report that MDM2 expression in lung Club or alveolar cells activates DNA replication specifically in lung progenitor cells only after chemical- or radiation-induced lung injury, irrespective of their p53 status. Activation of DNA replication by MDM2 triggered by injury leads to proliferation of lung progenitor cells and restoration of the lost epithelial layers. Mouse lung with no Mdm2 allele loses its ability to replicate DNA, whereas loss of 1 Mdm2 allele compromises this function, demonstrating the requirement of endogenous MDM2. We show that the p53-independent ability of MDM2 to activate Akt signaling is essential for initiating DNA replication in lung progenitor cells. Furthermore, MDM2 activates the Notch signaling pathway and expression of EMT markers, indicative of epithelial regeneration. This is the first report to our knowledge demonstrating a direct p53-independent participation of MDM2 in progenitor cell proliferation and epithelial repair after lung injury, distinct from a p53-degrading antiapoptotic effect preventing injury. |
| Databáze: | OpenAIRE |
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