Inactivation of sestrin 2 induces TGF-beta signaling and partially rescues pulmonary emphysema in a mouse model of COPD

Frank Wempe; Silke De-Zolt; Katri Koli; Thorsten Bangsow; Nirmal Parajuli; Rio Dumitrascu; Anja Sterner-Kock; Norbert Weissmann; Jorma Keski-Oja; Harald von Melchner

doi:10.1242/dmm.004234

Inactivation of sestrin 2 induces TGF-beta signaling and partially rescues pulmonary emphysema in a mouse model of COPD

Dis Model Mech. 2010 Mar-Apr;3(3-4):246-53. doi: 10.1242/dmm.004234. Epub 2010 Jan 27.

Authors

Frank Wempe¹, Silke De-Zolt, Katri Koli, Thorsten Bangsow, Nirmal Parajuli, Rio Dumitrascu, Anja Sterner-Kock, Norbert Weissmann, Jorma Keski-Oja, Harald von Melchner

Affiliation

¹ Department of Molecular Hematology, University of Frankfurt Medical School, 60590 Frankfurt am Main, Germany.

PMID: 20106877
DOI: 10.1242/dmm.004234

Abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Cigarette smoking has been identified as one of the major risk factors and several predisposing genetic factors have been implicated in the pathogenesis of COPD, including a single nucleotide polymorphism (SNP) in the latent transforming growth factor (TGF)-beta binding protein 4 (Ltbp4)-encoding gene. Consistent with this finding, mice with a null mutation of the short splice variant of Ltbp4 (Ltbp4S) develop pulmonary emphysema that is reminiscent of COPD. Here, we report that the mutational inactivation of the antioxidant protein sestrin 2 (sesn2) partially rescues the emphysema phenotype of Ltbp4S mice and is associated with activation of the TGF-beta and mammalian target of rapamycin (mTOR) signal transduction pathways. The results suggest that sesn2 could be clinically relevant to patients with COPD who might benefit from antagonists of sestrin function.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Animals
Disease Models, Animal
Enzyme Induction
Fibroblasts / metabolism
Fibroblasts / pathology
Gene Silencing*
Intracellular Signaling Peptides and Proteins
Latent TGF-beta Binding Proteins / deficiency
Lung / metabolism
Lung / pathology
Mice
Mice, Knockout
Mutation / genetics
Nuclear Proteins
Peroxidases
Protein Serine-Threonine Kinases / biosynthesis
Proteins / genetics*
Pulmonary Disease, Chronic Obstructive / complications
Pulmonary Disease, Chronic Obstructive / enzymology
Pulmonary Disease, Chronic Obstructive / metabolism*
Pulmonary Disease, Chronic Obstructive / pathology
Pulmonary Emphysema / complications
Pulmonary Emphysema / enzymology
Pulmonary Emphysema / metabolism*
Pulmonary Emphysema / pathology
Reactive Oxygen Species / metabolism
Signal Transduction*
TOR Serine-Threonine Kinases
Transforming Growth Factor beta / metabolism*

Substances

Intracellular Signaling Peptides and Proteins
Latent TGF-beta Binding Proteins
Nuclear Proteins
Proteins
Reactive Oxygen Species
Transforming Growth Factor beta
Peroxidases
Sesn2 protein, mouse
mTOR protein, mouse
Protein Serine-Threonine Kinases
TOR Serine-Threonine Kinases