title: Regulation of airway and alveolar epithelial cell apoptosis by p53-Induced plasminogen activator inhibitor-1 during cigarette smoke exposure injury.
abstract: Increased expression of tumor suppressor protein p53 and of plasminogen activator inhibitor (PAI)-1 is associated with cigarette smoke (CS) exposure-induced lung epithelial injury. p53 induces PAI-1 through mRNA stabilization in lung epithelial cells. However, it is unclear how this process affects lung epithelial damage. Here, we show that CS induces p53 and PAI-1 expression and apoptosis in cultured Beas2B and primary alveolar type (AT)II cells. CS exposure augmented binding of p53 protein with PAI-1 mRNA. Inhibition of p53 from binding to PAI-1 mRNA through expression of p53-binding 70 nt PAI-1 mRNA 3'UTR sequences suppressed CS-induced PAI-1 expression. Treatment of Beas2B cells with caveolin-1 scaffolding domain peptide (CSP) suppressed p53 expression and p53-PAI-1 mRNA interaction. These changes were associated with parallel inhibition of CS-induced PAI-1 expression and apoptosis in Beas2B cells. Wild-type mice exposed to passive CS likewise show augmented p53 and PAI-1 with parallel induction of ATII cell apoptosis, whereas mice deficient for p53 or PAI-1 expression resisted apoptosis of ATII cells. CSP suppressed CS-induced ATII cell apoptosis in wild-type mice and abrogated p53-PAI-1 mRNA interaction with parallel inhibition of p53 and PAI-1 expression. The protection against ATII cell apoptosis by CSP involves inhibition of passive CS-induced proapoptotic Bax and Bak expression and restoration of the prosurvival proteins Bcl-X(L). These observations demonstrate that inhibition of p53 binding to PAI-1 mRNA 3'UTR attenuates CS-induced ATII cell apoptosis. This presents a novel link between p53-mediated PAI-1 expression and CS-induced ATII cell apoptosis.
authors.affiliation: The Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler, 11937 US HWY 271, Lab C-6, Tyler, TX, 75708, USA. sreerama.shetty@uthct.edu
authors.forename: Shwetha K
authors.initials: SK
authors.lastname: Shetty
authors.forename: Yashodhar P
authors.initials: YP
authors.lastname: Bhandary
authors.forename: Amarnath S
authors.initials: AS
authors.lastname: Marudamuthu
authors.forename: Daniel
authors.initials: D
authors.lastname: Abernathy
authors.forename: Thirunavukkarasu
authors.initials: T
authors.lastname: Velusamy
authors.forename: Barry
authors.initials: B
authors.lastname: Starcher
authors.forename: Sreerama
authors.initials: S
authors.lastname: Shetty
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D001992:Bronchoalveolar Lavage Fluid; D051242:Caveolin 1 / Q000494:pharmacology; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000009:adverse effects*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051242:Caveolin 1; D010446:Peptide Fragments; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D012906:Smoke; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53