Transcriptional Stimulation of the Surfactant Protein B Gene by STAT3 in Respiratory Epithelial Cells

Yan, Cong; Naltner, Angela; Martin, Michelle; Naltner, Michael; Fangman, Jessica M.; Gurel, Okyanus

doi:10.1074/jbc.m109986200

Cited by 66 publications

(100 citation statements)

References 36 publications

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“…While its potential role in lung morphogenesis or function is presently unknown, in vitro studies demonstrated that STAT-3 regulated the expression of surfactant protein B (SP-B), binding and activating cis-active elements in the SftpB gene promoter (6). Its potential role in the regulation of surfactant homeostasis in respiratory epithelial cells in vivo has not been evaluated, however.…”

Section: For Review)mentioning

confidence: 99%

Stat-3 is required for pulmonary homeostasis during hyperoxia

Hokuto¹,

Ikegami²,

Yoshida³

et al. 2004

J. Clin. Invest.

113

121

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Acute lung injury syndromes remain common causes of morbidity and mortality in adults and children. Cellular and physiologic mechanisms maintaining pulmonary homeostasis during lung injury remain poorly understood. In the present study, the Stat-3 gene was selectively deleted in respiratory epithelial cells by conditional expression of Cre-recombinase under control of the surfactant protein C gene promoter. Cell-selective deletion of Stat-3 in respiratory epithelial cells did not alter prenatal lung morphogenesis or postnatal lung function. However, exposure of adult Stat-3-deleted mice to 95% oxygen caused a more rapidly progressive lung injury associated with alveolar capillary leak and acute respiratory distress. Epithelial cell injury and inflammatory responses were increased in the Stat-3-deleted mice. Surfactant proteins and lipids were decreased or absent in alveolar lavage material. Intratracheal treatment with exogenous surfactant protein B improved survival and lung histology in Stat-3-deleted mice during hyperoxia. Expression of Stat-3 in respiratory epithelial cells is not required for lung formation, but plays a critical role in maintenance of surfactant homeostasis and lung function during oxygen injury. 29Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remain a common cause of morbidity and mortality in both infants and adults following infection, trauma, inhalation of toxicants, and drowning. The recent severe acute respiratory syndrome (SARS) outbreak emphasizes the severity of pulmonary outcomes associated with ALI (7). ARDS is associated with surfactant deficiency and dysfunction (8, 9), including abnormalities in surfactant lipids and proteins. Of the surfactant proteins, SP-B is required for maintenance of lung function in both newborn and postnatal periods (10, 11) and for adaptation to lung injury following infection or oxygen exposure. To assess the role of STAT-3 in lung function, we used a conditional system to express Cre-recombinase to selectively delete the Stat-3 gene in bronchiolar and alveolar epithelial cells of the mouse lung. MethodsGene construction and PCR. We generated SP-C-rtTA tg/-transgenic mice and (tetO) 7 CMV-Cre tg/tg or (tetO) 7 CMVCre tg/-mice as described previously (12, 13 -C-rtTA, (tetO) 7 CMV-Cre and Stat-3 flx genes using the primers 5′-GAC ACA TAT AAG ACC CTG GCTA-3′ and 5′-AAA ATC TTG CCA GCT TTC CC-3′ for SP-C-rtTA; 5′-TGC CAC CAA GTG ACA GCA ATG-3′ and 5′-AGA GAC GGA AAT CCA TCG CTCG-3′ for (tetO) 7 CMV-Cre; and 5′-CCT GAA GAC CAA GTT CAT CTG TGT GAC-3′ and 5′-CAC ACA AGC CAT CAA ACT CTG GTC TCC-3′ for Stat-3 flx . Triple transgenic (Stat-3 ∆/∆ ) and nondeleted littermate (Stat-3 flx/flx ) control mice were used for the experiments.Animal use and doxycycline administration. Transgenic Stat-3 ∆/∆ and control mice were kept in a pathogen-free vivarium according to institutional guidelines until oxygen exposure. Doxycycline was administered to the dams in the food at a concentration of 625 mg/kg (Harlan Teklad, Madison, Wisconsin, U...

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Section: For Review)mentioning

confidence: 99%

Stat-3 is required for pulmonary homeostasis during hyperoxia

Hokuto¹,

Ikegami²,

Yoshida³

et al. 2004

J. Clin. Invest.

113

121

View full text Add to dashboard Cite

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“…The centralized homeodomain is known to bind to other transcription factors, including retinoic acid receptors (RARs) (Yan et al, 2001), zinc finger GATA transcription-6 (GATA-6) (Liu et al, 2002;Weidenfeld et al, 2002), and nuclear factor of activated T cells (NFAT) (Dave et al, 2004). Finally, the COOH-terminus functionally interacts with the DNA repair protein thymine DNA glycosylase (TDG) (Missero et al, 2001), other transcriptional coactivators such as p300 (Bachurski et al, 2003;Grasberger et al, 2005), SRC-3, SRC-2, BR22 (amino acid 6-206) (Yang et al, 2001;2003), poly(adenosine diphosphate-ribose) polymerase-1 (PARP-1), PARP-2 (Maeda et al, 2006), and other transcription factors such as nuclear factor κB (NF-κB) (Islam and Mendelson, 2006), signal transducers and activators of transcription 3 (STAT3) (Yan et al, 2002), Drosophila mothers against decapentaplegic 3 (SMAD3) (Li et al, 2002), nuclear factor I (NFI) (Missero et al, 2001), and ezrinradixin-moesin (ERM) (Lin et al, 2006).…”

Section: Structure Of the Nkx2-1 Gene And Protein And Its Biologicalmentioning

confidence: 99%

Nkx2-1: a novel tumor biomarker of lung cancer

Lin

Ruan

et al. 2012

J. Zhejiang Univ. Sci. B

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Nkx2-1 (Nkx homeobox-1 gene), also known as TTF-1 (thyroid transcription factor-1), is a tissue-specific transcription factor of the thyroid, lung, and ventral forebrain. While it has been shown to play a critical role in lung development and lung cancer differentiation and morphogenesis, molecular mechanisms mediating Nkx2-1 cell-and tissue-specific expression in normal and cancerous lungs have yet to be fully elucidated. The recent identification of prognostic biomarkers in lung cancer, particularly in lung adenocarcinoma (ADC), and the different reactivity of patients to chemotherapeutic drugs have opened new avenues for evaluating patient survival and the development of novel effective therapeutic strategies. The function of Nkx2-1 as a proto-oncogene was recently characterized and the gene is implicated as a contributory factor in lung cancer development. In this review, we summarize the role of this transcription factor in the development, diagnosis, and prognosis of lung cancer in the hope of providing insights into the utility of Nkx2-1 as a novel biomarker of lung cancer.

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“…The CCSP-rtTA transgenic mice were genotyped with an upstream primer corresponding to the CCSP promoter sequence (5Ј-ACTGCCCATTGCCCAAACAC-3Ј) and a downstream primer corresponding to the rtTA code region sequence (5Ј-AAAATCTTGC CAGCTTTCCCC-3Ј). CCSP-rtTA/(teto) 7 -CMV-Stat3C double-transgenic mice were generated from cross-breeding of the CCSP-rtTA transgenic mice and (teto) 7 -CMV-Stat3C transgenic mice.…”

Section: Generation Of Doxycycline-controlled Stat3c Transgenic Micementioning

confidence: 99%

“…In the absence of SP-B, neonatal lungs are collapsed during respiratory cycles that cause death after birth (10,11). Stat3 stimulates SP-B gene expression in respiratory epithelial cells in a synergistic manner with retinoid acid receptors (7,8). In an animal system, in which the Stat3 allele is selectively deleted in respiratory epithelial cells, surfactant proteins and lipids are decreased or absent in alveolar lavage material during hyperoxia.…”

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confidence: 99%

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Overexpression of Stat3C in Pulmonary Epithelium Protects against Hyperoxic Lung Injury

Lian

Qin²,

Hossain

et al. 2005

The Journal of Immunology

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Acute lung injury is a side effect of therapy with a high concentration of inspired oxygen in patients. The molecular mechanism underlining this effect is poorly understood. In this study, we report that overexpression of Stat3C, a constitutive active form of STAT3, in respiratory epithelial cells of a doxycycline-controlled double-transgenic mouse system protects lung from inflammation and injury caused by hyperoxia. In this mouse line, >50% of transgenic mice survived exposure to 95% oxygen at day 7, compared with 0% survival of wild-type mice. Overexpression of STAT3C delays acute capillary leakage and neutrophil infiltration into the alveolar region. This protection is mediated at least partially through inhibition of hyperoxia-induced synthesis and release of matrix metalloproteinase (MMP)-9 and MMP-12 by neutrophils and alveolar resident cells. In some MMP-9−/− mice, prolonged survival was observed under hyperoxic condition. The finding supports a concept that activation of the Stat3 pathway plays a role to prevent hyperoxia-induced inflammation and injury in the lung.

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Transcriptional Stimulation of the Surfactant Protein B Gene by STAT3 in Respiratory Epithelial Cells

Cited by 66 publications

References 36 publications

Stat-3 is required for pulmonary homeostasis during hyperoxia

Stat-3 is required for pulmonary homeostasis during hyperoxia

Nkx2-1: a novel tumor biomarker of lung cancer

Overexpression of Stat3C in Pulmonary Epithelium Protects against Hyperoxic Lung Injury

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