Smad and p38-MAPK signaling mediates apoptotic effects of transforming growth factor-β1 in human airway epithelial cells

Undevia, Nidhi S.; Dorscheid, Delbert R.; Marroquin, Bertha A.; Gugliotta, Wendy L.; Tse, Roberta; White, Steven R.

doi:10.1152/ajplung.00044.2004

Cited by 43 publications

(40 citation statements)

References 77 publications

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“…p38 MAPK transduces the apoptotic signal of TGF-␤1, whereas ERK1͞2 relays prosurvival signaling in a variety of cells including endothelial cells (37)(38)(39). In TGF-␤1-treated endothelial cells p38 MAPK activation occurred only in cells that showed the nuclear chromatin condensation typical of apoptosis, whereas cells devoid of apoptotic nuclei showed no active p38 MAPK (Fig.…”

Section: Tgf-␤1 Induction Of Endothelial Cell Apoptosis Requires Vegfmentioning

confidence: 97%

VEGF, a prosurvival factor, acts in concert with TGF-β1 to induce endothelial cell apoptosis

Ferrari

Pintucci

Seghezzi

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

143

147

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VEGF and TGF-␤1 are potent angiogenesis inducers with opposing effects on endothelial cells. TGF-␤1 induces apoptosis; VEGF protects endothelial cells from apoptosis. We found that TGF-␤1 promotes endothelial cell expression of FGF-2, which up-regulates VEGF synthesis. Inhibition of VEGF signaling through VEGF receptor 2 (flk-1) abrogates TGF-␤1-induced apoptosis and p38 MAPK activation. Inhibition of p38 MAPK blocks TGF-␤1-induced apoptosis, showing that VEGF͞flk-1-mediated activation of p38 MAPK is required for TGF-␤1 induction of apoptosis. In the absence of TGF-␤1, VEGF activates p38 MAPK and promotes endothelial cell survival. However, in context with TGF-␤1, VEGF͞flk-1-mediated activation of p38 MAPK results in apoptosis. Thus, cross-talk between TGF-␤1 and VEGF signaling converts VEGF͞flk-1-activated p38 MAPK into a proapoptotic signal. This finding illustrates an unexpected role of VEGF and indicates that VEGF can be pharmacologically converted into an apoptotic factor, a novel approach to antiangiogenesis therapy.angiogenesis ͉ MAPK kinase ͉ p38 ͉ VEGF receptor ͉ cancer

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Section: Tgf-␤1 Induction Of Endothelial Cell Apoptosis Requires Vegfmentioning

confidence: 97%

VEGF, a prosurvival factor, acts in concert with TGF-β1 to induce endothelial cell apoptosis

Ferrari

Pintucci

Seghezzi

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

143

147

View full text Add to dashboard Cite

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“…To further examine cell survival mechanisms that might be altered by CS but restored by losartan, we explored TGF-β-induced pathways that converge onto canonical survival kinase cascades (p21, p38, JNK, and PI3K/Akt) (18)(19)(20)(21). We focused on p21 (proapoptotic/antiapoptotic), p38 (proapoptotic), JNK (proapoptotic), and akt (antiapoptotic), since these can be modulated by TGF-β.…”

Section: Figurementioning

confidence: 99%

Angiotensin receptor blockade attenuates cigarette smoke–induced lung injury and rescues lung architecture in mice

et al. 2012

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Chronic obstructive pulmonary disease (COPD) is a prevalent smoking-related disease for which no diseasealtering therapies currently exist. As dysregulated TGF-β signaling associates with lung pathology in patients with COPD and in animal models of lung injury induced by chronic exposure to cigarette smoke (CS), we postulated that inhibiting TGF-β signaling would protect against CS-induced lung injury. We first confirmed that TGF-β signaling was induced in the lungs of mice chronically exposed to CS as well as in COPD patient samples. Importantly, key pathological features of smoking-associated lung disease in patients, e.g., alveolar injury with overt emphysema and airway epithelial hyperplasia with fibrosis, accompanied CS-induced alveolar cell apoptosis caused by enhanced TGF-β signaling in CS-exposed mice. Systemic administration of a TGF-β-specific neutralizing antibody normalized TGF-β signaling and alveolar cell death, conferring improved lung architecture and lung mechanics in CS-exposed mice. Use of losartan, an angiotensin receptor type 1 blocker used widely in the clinic and known to antagonize TGF-β signaling, also improved oxidative stress, inflammation, metalloprotease activation and elastin remodeling. These data support our hypothesis that inhibition of TGF-β signaling through angiotensin receptor blockade can attenuate CS-induced lung injury in an established murine model. More importantly, our findings provide a preclinical platform for the development of other TGF-β-targeted therapies for patients with COPD.

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“…Studies on pulmonary epithelial cells suggest that TGF-β activates p38 MAPK within 30 min and inhibition of p38 MAPK can significantly reduce TGF-β1-dependent gene expression for the extracellular matrix-related gene fibronectin (16,17). In addition, blockade of Smad pathway caused by Smad7 overexpression, can result in TGF-β1-induced apoptosis mediated by p38 MAPK signaling (18).…”

Section: Introductionmentioning

confidence: 99%

Crosstalk between p38 and Smad3 through TGF-β1 in JEG-3 choriocarcinoma cells

Tan

Zhang

et al. 2013

International Journal of Oncology

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Abstract. Choriocarcinoma is a highly malignant trophoblastic tumor related to pregnancy that often occurs with a complete hydatidiform mole. It grows quickly and can also widely metastasize to other organs or tissues through both the venous and lymphatic systems. The transforming growth factor-β1 (TGF-β1) belongs to a growth factor superfamily and has been suggested to play a critical role in regulating the genesis and development of choriocarcinoma through a variety of Smad-independent pathways, including the p38 MAPK pathway. Previous studies indicated that TGF-β can activate the p38 MAPK pathway. In this study, we investigated Smad and p38 MAPK signaling in JEG-3 choriocarcinoma cells using p38 MAPK inhibitor and TGF-β receptor inhibitor. Immunofluorescence and western blot assays were used to detect the proteins in Smad and p38 MAPK pathways. Our data demonstrated that TGF-β can activate Smad3 and induce Smad3 translocation into the nucleus in JEG-3 cells. Blockade of the TGF-β pathway significantly reduced the expression levels of p38 and phospho-p38. p38 MAPK inhibitors (SB 203580) can attenuate TGF-β1-induced Smad3 expression and suppress the activation of smad3. These findings indicate crosstalk between p38 and smad3 through TGF-β1 in choriocarcinoma cells.

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Smad and p38-MAPK signaling mediates apoptotic effects of transforming growth factor-β1 in human airway epithelial cells

Cited by 43 publications

References 77 publications

VEGF, a prosurvival factor, acts in concert with TGF-β1 to induce endothelial cell apoptosis

VEGF, a prosurvival factor, acts in concert with TGF-β1 to induce endothelial cell apoptosis

Angiotensin receptor blockade attenuates cigarette smoke–induced lung injury and rescues lung architecture in mice

Crosstalk between p38 and Smad3 through TGF-β1 in JEG-3 choriocarcinoma cells

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