Investigating sestrin 2 (sesn2) control of TGF-beta, mTOR and PDGF signaling and its potential significance in the development of chronic obstructive pulmonary disease (COPD)
Final Report Abstract
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. COPD is caused by chronic exposure to cigarette smoke and/or other environmental pollutants that are believed to induce reactive oxygen species (ROS) that gradually disrupt signaling pathways responsible for maintaining lung integrity. Here we identified the antioxidant protein Sestrin 2 (Sesn2) as a repressor of PDGFRβ signaling and PDGFRβ signaling as an upstream regulator of alveolar maintenance programs. In mice, the mutational inactivation of Sesn2 prevents the development of cigarette-smoke induced pulmonary emphysema by upregulating PDGFRβ expression via a selective accumulation of intracellular superoxide anions (O2-). In addition, we found SESN2 overexpressed and PDGFRβ downregulated in the emphysematous lungs of patients with COPD and to a lesser extent in human lungs of habitual smokers without COPD, implicating a negative SESN2/PDGFRβ interrelationship in the pathogenesis of COPD. Taken together, our results imply that SESN2 could serve as both a biomarker and as a drug target in the clinical management of COPD.
Publications
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An animal model exhibiting cancer, pulmonary emphysema and cardiomyopathy. EP1416791B1
von Melchner H, Thorey I, Wempe F, Sterner-Kock A, Keski-Oja J
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Animal model for the selection and validation of agents active against pulmonary emphysema and colorectal cancer. EP2066794B1
von Melchner H, Wempe F, De-Zolt S
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(2007) Splinkerette PCR for more efficient characterization of gene trap events. Nat Genet 39: 933-934
Horn C, Hansen J, Schnütgen F, Seisenberger C, Floss T, Irgang M, De-Zolt S, Wurst W, von Melchner H, Noppinger PR
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(2009) Dual functions for LTBP in lung development: LTBP-4 independently modulates elastogenesis and TGF-beta activity. J Cell Physiol 219: 14-22
Dabovic B, Chen Y, Choi J, Vassallo M, Dietz HC, Ramirez F, von Melchner H, Davis EC, Rifkin DB
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(2010) Inactivation of sestrin 2 induces TGF-beta signaling and partially rescues pulmonary emphysema in a mouse model of COPD. Dis Model Mech 3: 246-253
Wempe F, De-Zolt S, Koli K, Bangsow T, Parajuli N, Dumitrascu R, Sterner-Kock A, Weissmann N, Keski-Oja J, von Melchner H
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(2010) Redox signaling and reactive oxygen species in hypoxic pulmonary vasoconstriction. Resp Physiol Neurobiol 174: 282-291
Fuchs B, Sommer N, Dietrich A, Schermuly RT, Ghofrani HA, Grimminger F, Seeger W, Gudermann T, Weissmann N
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(2011) Hypoxia enhances platelet-derived growth factor signaling in the pulmonary vasculature by down-regulation of protein tyrosine phosphatases. Am J Resp Crit Care Med 183: 1092-1102
ten Freyhaus H, Dagnell M, Leuchs M, Vantler M, Berghausen EM, Caglayan E, Weissmann N, Dahal BK, Schermuly RT, Ostman A, Kappert K, Rosenkranz S
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(2011) Inducible NOS inhibition reverses tobacco-smoke-induced emphysema and pulmonary hypertension in mice. Cell 147: 293-305
Seimetz M, Parajuli N, Pichl A, Veit F, Kwapiszewska G, Weisel FC, Milger K, Egemnazarov B, Turowska A, Fuchs B, Nikam S, Roth M, Sydykov A, Medebach T, Klepetko W, Jaksch P, Dumitrascu R, Garn H, Voswinckel R, Kostin S, Seeger W, Schermuly RT, Grimminger F, Ghofrani HA, Weissmann N
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(2011) Resources for proteomics in mouse embryonic stem cells. Nat Methods 8: 103-104
Schnütgen F, Ehrmann F, Poser I, Hubner NC, Hansen J, Floss T, deVries I, Wurst W, Hyman A, Mann M, von Melchner H
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(2012). Hypoxia induces Kv channel current inhibition by increased NADPH oxidase-derived reactive oxygen species. Free Radic Biol Med, 52, 1033-1042
Mittal M, Gu XQ, Pak O, Pamenter ME, Haag D, Fuchs DB, Schermuly RT, Ghofrani HA, Brandes RP, Seeger W, Grimminger F, Haddad GG, & Weissmann N
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(2013). Antioxidant Activity of Sestrin 2 Controls Neuropathic Pain After Peripheral Nerve Injury. Antioxid Redox Signal
Kallenborn-Gerhardt W, Lu R, Syhr KM, Heidler J, von Melchner H, Geisslinger G, Bangsow T, & Schmidtko A
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(2013). Latent TGF-beta binding protein 4 promotes elastic fiber assembly by interacting with fibulin-5. Proc Natl Acad Sci USA, 110, 2852-2857
Noda K, Dabovic B, Takagi K, Inoue T, Horiguchi M, Hirai M, Fujikawa Y, Akama TO, Kusumoto K, Zilberberg L, Sakai LY, Koli K, Naitoh M, von Melchner H, Suzuki S, Rifkin DB, & Nakamura T
