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Am J Respir Crit Care Med. 2016 Jul 15;194(2):185-97. doi: 10.1164/rccm.201505-0999OC.

A Chronic Obstructive Pulmonary Disease Susceptibility Gene, FAM13A, Regulates Protein Stability of β-Catenin.

Author information

1
1 Channing Division of Network Medicine, Department of Medicine.
2
2 Division of Pulmonary and Critical Care Medicine, Department of Medicine.
3
3 The Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
4
4 Division of General Internal Medicine, Department of Medicine, and.
5
5 Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and.
6
6 Department of Medicine, Weill Cornell Medical College, New York, New York.
7
7 Pediatric Newborn Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Abstract

RATIONALE:

A genetic locus within the FAM13A gene has been consistently associated with chronic obstructive pulmonary disease (COPD) in genome-wide association studies. However, the mechanisms by which FAM13A contributes to COPD susceptibility are unknown.

OBJECTIVES:

To determine the biologic function of FAM13A in human COPD and murine COPD models and discover the molecular mechanism by which FAM13A influences COPD susceptibility.

METHODS:

Fam13a null mice (Fam13a(-/-)) were generated and exposed to cigarette smoke. The lung inflammatory response and airspace size were assessed in Fam13a(-/-) and Fam13a(+/+) littermate control mice. Cellular localization of FAM13A protein and mRNA levels of FAM13A in COPD lungs were assessed using immunofluorescence, Western blotting, and reverse transcriptase-polymerase chain reaction, respectively. Immunoprecipitation followed by mass spectrometry identified cellular proteins that interact with FAM13A to reveal insights on FAM13A's function.

MEASUREMENTS AND MAIN RESULTS:

In murine and human lungs, FAM13A is expressed in airway and alveolar type II epithelial cells and macrophages. Fam13a null mice (Fam13a(-/-)) were resistant to chronic cigarette smoke-induced emphysema compared with Fam13a(+/+) mice. In vitro, FAM13A interacts with protein phosphatase 2A and recruits protein phosphatase 2A with glycogen synthase kinase 3β and β-catenin, inducing β-catenin degradation. Fam13a(-/-) mice were also resistant to elastase-induced emphysema, and this resistance was reversed by coadministration of a β-catenin inhibitor, suggesting that FAM13A could increase the susceptibility of mice to emphysema development by inhibiting β-catenin signaling. Moreover, human COPD lungs had decreased protein levels of β-catenin and increased protein levels of FAM13A.

CONCLUSIONS:

We show that FAM13A may influence COPD susceptibility by promoting β-catenin degradation.

KEYWORDS:

FAM13A; cell proliferation; emphysema; protein stability; β-catenin

PMID:
26862784
PMCID:
PMC5003213
DOI:
10.1164/rccm.201505-0999OC
[Indexed for MEDLINE]
Free PMC Article

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