Distinct Roles for Mammalian Target of Rapamycin Complexes in the Fibroblast Response to Transforming Growth Factor-β

Rahimi, Rod A.; Andrianifahanana, Mahefatiana; Wilkes, Mark C.; Edens, Maryanne; Kottom, Theodore J.; Blenis, John; Leof, Edward B.

doi:10.1158/0008-5472.can-08-2146

Cited by 84 publications

(95 citation statements)

References 40 publications

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“…35 Overall, TGF-␤ is recognized as a potent growth inhibitor in cells of epithelial origin 36 -41 and a growth stimulator in fibroblast-type cells. 23,25,42 Although VICs are fibroblast-type cells, the anti-proliferative response in these fibroblasts could be partially explained by the fact that they are derived from surface endothelial cells that have undergone epithelial-to-mesenchymal transformation during embryonic development. 2 It is possible that VICs from adult heart valves still possess characteristics of valve endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-β Regulates the Growth of Valve Interstitial Cells in Vitro

Gotlieb

2011

The American Journal of Pathology

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Although valve interstitial cell (VIC) growth is an essential feature of injured and diseased valves, the regulation of VIC growth is poorly understood. Transforming growth factor (TGF)-␤ promotes VIC proliferation in early-stage wound repair; thus, herein, we tested the hypothesis that TGF-␤ regulates VIC proliferation under normal nonwound conditions using low-density porcine VIC monolayers. Cell numbers were counted during a 10-day period, whereas proliferation and apoptosis were quantified by bromodeoxyuridine staining and TUNEL, respectively. The extent of retinoblastoma protein phosphorylation and expression of cyclin D1, CDK 4, and p27 were compared using Western blot analysis. Adhesion was quantified using a trypsin adhesion assay, and morphological change was demonstrated by immunofluorescence localization of ␣-smooth muscle actin and vinculin. TGF-␤-treated VICs were rhomboid; significantly decreased in number, proliferation, and retinoblastoma protein phosphorylation; and concomitantly had decreased expression of cyclin D1/CDK4 and increased expression of p27. TGF-␤-treated VICs adhered better to substratum and had more vinculin plaques and ␣-smooth muscle actin stress fibers than did controls. Thus, the regulation of VIC growth by TGF-␤ is context dependent. TGF-␤ prevents excessive heart valve growth under normal physiological conditions while it promotes cell proliferation in the early stages of repair, when increased VICs are required.

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Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-β Regulates the Growth of Valve Interstitial Cells in Vitro

Gotlieb

2011

The American Journal of Pathology

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“…Our previous study observed that optimal Mn induced the high-abundance of TGF-β mRNA level in the intestine of grass carp . TGF-β could activate the TOR protein expression in mouse embryonic fibroblasts (Rahimi et al, 2009). Thus, Mn up-regulated the mRNA levels of TOR might be partially due to the high TGF-β level, which needs further investigations.…”

Section: Mn Up-regulated the Muscle Antioxidant-related Signaling Molmentioning

confidence: 96%

Nutritive values, flavor amino acids, healthcare fatty acids and flesh quality improved by manganese referring to up-regulating the antioxidant capacity and signaling molecules TOR and Nrf2 in the muscle of fish

Jiang

Tang

et al. 2016

Food Research International

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“…More recently, we further elaborated on this model of fibroblast-specific signaling by showing that TGF-␤ also activates the mammalian target of rapamycin complex-1 (mTORC1) specifically in fibroblasts through a pathway involving phosphatidyl-inositol-3Ј-kinase, protein kinase-B/Akt, and tuberin (PI3K 3 PKB/Akt 3 TSC2). In vitro, this pathway is inhibited by rapamycin and fibroblast proliferation is reduced (13).…”

mentioning

confidence: 99%

Noncanonical TGF-β pathways, mTORC1 and Abl, in renal interstitial fibrogenesis

Wang

Wilkes

Leof

et al. 2010

American Journal of Physiology-Renal Physiology

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116

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Renal interstitial fibrosis is a major determinant of renal failure in the majority of chronic renal diseases. Transforming growth factor-β (TGF-β) is the single most important cytokine promoting renal fibrogenesis. Recent in vitro studies identified novel non-smad TGF-β targets including p21-activated kinase-2 (PAK2), the abelson nonreceptor tyrosine kinase (c-Abl), and the mammalian target of rapamycin (mTOR) that are activated by TGF-β in mesenchymal cells, specifically in fibroblasts but less in epithelial cells. In the present studies, we show that non-smad effectors of TGF-β including PAK2, c-Abl, Akt, tuberin (TSC2), and mTOR are activated in experimental unilateral obstructive nephropathy in rats. Treatment with c-Abl or mTOR inhibitors, imatinib mesylate and rapamycin, respectively, each blocks noncanonical (non-smad) TGF-β pathways in the kidney in vivo and diminishes the number of interstitial fibroblasts and myofibroblasts as well as the interstitial accumulation of extracellular matrix proteins. These findings indicate that noncanonical TGF-β pathways are activated during the early and rapid renal fibrogenesis of obstructive nephropathy. Moreover, the current findings suggest that combined inhibition of key regulators of these non-smad TGF-β pathways even in dose-sparing protocols are effective treatments in renal fibrogenesis.

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Distinct Roles for Mammalian Target of Rapamycin Complexes in the Fibroblast Response to Transforming Growth Factor-β

Abstract: Transforming growth factor-B

Cited by 84 publications

References 40 publications

Transforming Growth Factor-β Regulates the Growth of Valve Interstitial Cells in Vitro

Transforming Growth Factor-β Regulates the Growth of Valve Interstitial Cells in Vitro

Nutritive values, flavor amino acids, healthcare fatty acids and flesh quality improved by manganese referring to up-regulating the antioxidant capacity and signaling molecules TOR and Nrf2 in the muscle of fish

Noncanonical TGF-β pathways, mTORC1 and Abl, in renal interstitial fibrogenesis

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