Mouse protocadherin-1 gene expression is regulated by cigarette smoke exposure in vivo

PLoS One. 2014 Jul 3;9(7):e98197. doi: 10.1371/journal.pone.0098197. eCollection 2014.

Abstract

Protocadherin-1 (PCDH1) is a novel susceptibility gene for airway hyperresponsiveness, first identified in families exposed to cigarette smoke and is expressed in bronchial epithelial cells. Here, we asked how mouse Pcdh1 expression is regulated in lung structural cells in vivo under physiological conditions, and in both short-term cigarette smoke exposure models characterized by airway inflammation and hyperresponsiveness and chronic cigarette smoke exposure models. Pcdh1 gene-structure was investigated by Rapid Amplification of cDNA Ends. Pcdh1 mRNA and protein expression was investigated by qRT-PCR, western blotting using isoform-specific antibodies. We observed 87% conservation of the Pcdh1 nucleotide sequence, and 96% conservation of the Pcdh1 protein sequence between men and mice. We identified a novel Pcdh1 isoform encoding only the intracellular signalling motifs. Cigarette smoke exposure for 4 consecutive days markedly reduced Pcdh1 mRNA expression in lung tissue (3 to 4-fold), while neutrophilia and airway hyperresponsiveness was induced. Moreover, Pcdh1 mRNA expression in lung tissue was reduced already 6 hours after an acute cigarette-smoke exposure in mice. Chronic exposure to cigarette smoke induced loss of Pcdh1 protein in lung tissue after 2 months, while Pcdh1 protein levels were no longer reduced after 9 months of cigarette smoke exposure. We conclude that Pcdh1 is highly homologous to human PCDH1, encodes two transmembrane proteins and one intracellular protein, and is regulated by cigarette smoke exposure in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bronchi / metabolism*
  • Bronchi / pathology
  • Cadherins / biosynthesis*
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Gene Expression Regulation*
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Protein Isoforms / biosynthesis
  • Respiratory Mucosa / metabolism*
  • Respiratory Mucosa / pathology
  • Smoking / adverse effects
  • Smoking / metabolism*

Substances

  • Cadherins
  • Pcdh1 protein, mouse
  • Protein Isoforms

Grant support

This study was supported by research grants from the Netherlands’ Lung Foundation (project NAF 3.2.09.055), the Stichting Astmabestrijding (SAB 2010/043) and the EU-funded FP6 project Gabriel (a multidisciplinary study to identify the genetic and environmental causes of asthma). GHK has received grant support from the University Medical Center Groningen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.