Transforming Growth Factor-β Receptor Type 1 (TGFβRI) Kinase Activity but Not p38 Activation Is Required for TGFβRI-Induced Myofibroblast Differentiation and Profibrotic Gene Expression

Kapoun, Ann M.; Gaspar, N. J.; Wang, Ying; Damm, Debby; Liu, Yuwang; O’Young, Gilbert; Quon, Diana; Lam, Andrew; Munson, Kimberly; Tran, Thomas-Toan; Jing, Ying; Murphy, Alison; Dugar, Sundeep; Chakravarty, Sarvajit; Protter, Andrew A.; Wen, Fuqiang; Liu, Xiangde; Rennard, Stephen I.; Higgins, Linda S.

doi:10.1124/mol.105.021600

Cited by 66 publications

(63 citation statements)

References 41 publications

(33 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The ␣ 1 chains of collagens I and III, and MMP-1, MMP-2, and TIMP-3 were not TGF-␤-inducible in 21% O 2 , which is consistent with other reports (21) illustrating that none of these genes are normally TGF-␤ inducible in fibroblasts, in contrast, for example, to collagens IV, VIII, and XV. However, levels of mRNA encoding TIMP-1 (Fig.…”

Section: Effect Of Hyperoxia On Tgf-␤-and Bmp-induced Proliferation Osupporting

confidence: 82%

Hyperoxia modulates TGF-β/BMP signaling in a mouse model of bronchopulmonary dysplasia

Alejandre-Alcázar

Kwapiszewska²,

Reiss³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

210

128

View full text Add to dashboard Cite

-Prematurely born infants who require oxygen therapy often develop bronchopulmonary dysplasia (BPD), a debilitating disorder characterized by pronounced alveolar hypoplasia. Hyperoxic injury is believed to disrupt critical signaling pathways that direct lung development, causing BPD. We investigated the effects of normobaric hyperoxia on transforming growth factor (TGF)-␤ and bone morphogenetic protein (BMP) signaling in neonatal C57BL/6J mice exposed to 21% or 85% O2 between postnatal days P1 and P28. Growth and respiratory compliance were significantly impaired in pups exposed to 85% O2, and these pups also exhibited a pronounced arrest of alveolarization, accompanied by dysregulated expression and localization of both receptor (ALK-1, ALK-3, ALK-6, and the TGF-␤ type II receptor) and Smad (Smads 1, 3, and 4) proteins. TGF-␤ signaling was potentiated, whereas BMP signaling was impaired both in the lungs of pups exposed to 85% O2 as well as in MLE-12 mouse lung epithelial cells and NIH/3T3 and primary lung fibroblasts cultured in 85% O2. After exposure to 85% O2, primary alveolar type II cells were more susceptible to TGF-␤-induced apoptosis, whereas primary pulmonary artery smooth muscle cells were unaffected. Exposure of primary lung fibroblasts to 85% O2 significantly enhanced the TGF-␤-stimulated production of the ␣1 subunit of type I collagen (I␣1), tissue inhibitor of metalloproteinase-1, tropoelastin, and tenascin-C. These data demonstrated that hyperoxia significantly affects TGF-␤/BMP signaling in the lung, including processes central to septation and, hence, alveolarization. The amenability of these pathways to genetic and pharmacological manipulation may provide alternative avenues for the management of BPD.

show abstract

Section: Effect Of Hyperoxia On Tgf-␤-and Bmp-induced Proliferation Osupporting

confidence: 82%

Hyperoxia modulates TGF-β/BMP signaling in a mouse model of bronchopulmonary dysplasia

Alejandre-Alcázar

Kwapiszewska²,

Reiss³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

210

128

View full text Add to dashboard Cite

show abstract

“…SD-208 has an IC 50 value of 49 nM when measured by direct enzymatic assay of TGF␤RI kinase activity in vitro. It is 100-fold less specific for TGF␤RII and is more than 17-fold less specific for related kinases (Kapoun et al, 2006).…”

Section: Methodsmentioning

confidence: 99%

“…The next day, they were treated with SD-208 (31.25-1000 nM) for 15 min before the addition of TGF␤1 (2 ng/ml). After 65 min, cell lysates were prepared and analyzed by Western blot as described previously (Kapoun et al, 2006).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Transforming Growth Factor β Signaling Reduces Pancreatic Adenocarcinoma Growth and Invasiveness

Gaspar¹,

Li²,

Kapoun³

et al. 2007

Mol Pharmacol

Self Cite

117

View full text Add to dashboard Cite

Transforming growth factor ␤ (TGF␤) is a pleiotropic factor that regulates cell proliferation, angiogenesis, metastasis, and immune suppression. Dysregulation of the TGF␤ pathway in tumor cells often leads to resistance to the antiproliferative effects of TGF␤ while supporting other cellular processes that promote tumor invasiveness and growth. In the present study, SD-208, a 2,4-disubstituted pteridine, ATP-competitive inhibitor of the TGF␤ receptor I kinase (TGF␤RI), was used to inhibit cellular activities and tumor progression of PANC-1, a human pancreatic tumor line. SD-208 blocked TGF␤-dependent Smad2 phosphorylation and expression of TGF␤-inducible proteins in cell culture. cDNA microarray analysis and functional gene clustering identified groups of TGF␤-regulated genes involved in metastasis, angiogenesis, cell proliferation, survival, and apoptosis. These gene responses were inhibited by SD-208. Using a Boyden chamber motility assay, we demonstrated that SD-208 inhibited TGF␤-stimulated invasion in vitro. An orthotopic xenograft mouse model revealed that SD-208 reduced primary tumor growth and decreased the incidence of metastasis in vivo. Our findings suggest mechanisms through which TGF␤ signaling may promote tumor progression in pancreatic adenocarcinoma. Moreover, they suggest that inhibition of TGF␤RI with a small-molecule inhibitor may be effective as a therapeutic approach to treat human pancreatic cancer.

show abstract

“…After 4 h, 60 mg/kg of SD208 in 1% methylcellulose or vehicle were given orally, twice daily for 4 days. SD208 (SCIOS) is a TGF-␤ receptor antagonist (18). Unilateral IRI (UIRI) was produced in 250-to 300-g male Sprague-Dawley rats under pentobarbital sodium anesthesia at 37°C.…”

Section: Animalsmentioning

confidence: 99%

PTEN loss defines a TGF-β-induced tubule phenotype of failed differentiation and JNK signaling during renal fibrosis

Lan

Geng

Polichnowski

et al. 2012

American Journal of Physiology-Renal Physiology

105

View full text Add to dashboard Cite

We investigated the signaling basis for tubule pathology during fibrosis after renal injury. Numerous signaling pathways are activated physiologically to direct tubule regeneration after acute kidney injury (AKI) but several persist pathologically after repair. Among these, transforming growth factor (TGF)-β is particularly important because it controls epithelial differentiation and profibrotic cytokine production. We found that increased TGF-β signaling after AKI is accompanied by PTEN loss from proximal tubules (PT). With time, subpopulations of regenerating PT with persistent loss of PTEN (phosphate and tension homolog) failed to differentiate, became growth arrested, expressed vimentin, displayed profibrotic JNK activation, and produced PDGF-B. These tubules were surrounded by fibrosis. In contrast, PTEN recovery was associated with epithelial differentiation, normal tubule repair, and less fibrosis. This beneficial outcome was promoted by TGF-β antagonism. Tubule-specific induction of TGF-β led to PTEN loss, JNK activation, and fibrosis even without prior AKI. In PT culture, high TGF-β depleted PTEN, inhibited differentiation, and activated JNK. Conversely, TGF-β antagonism increased PTEN, promoted differentiation, and decreased JNK activity. Cre-Lox PTEN deletion suppressed differentiation, induced growth arrest, and activated JNK. The low-PTEN state with JNK signaling and fibrosis was ameliorated by contralateral nephrectomy done 2 wk after unilateral ischemia, suggesting reversibility of the low-PTEN dysfunctional tubule phenotype. Vimentin-expressing tubules with low-PTEN and JNK activation were associated with fibrosis also after tubule-selective AKI, and with human chronic kidney diseases of diverse etiology. By preventing tubule differentiation, the low-PTEN state may provide a platform for signals initiated physiologically to persist pathologically and cause fibrosis after injury.

show abstract

Transforming Growth Factor-β Receptor Type 1 (TGFβRI) Kinase Activity but Not p38 Activation Is Required for TGFβRI-Induced Myofibroblast Differentiation and Profibrotic Gene Expression

Cited by 66 publications

References 41 publications

Hyperoxia modulates TGF-β/BMP signaling in a mouse model of bronchopulmonary dysplasia

Hyperoxia modulates TGF-β/BMP signaling in a mouse model of bronchopulmonary dysplasia

Inhibition of Transforming Growth Factor β Signaling Reduces Pancreatic Adenocarcinoma Growth and Invasiveness

PTEN loss defines a TGF-β-induced tubule phenotype of failed differentiation and JNK signaling during renal fibrosis

Contact Info

Product

Resources

About