Mammalian dwarfins are phosphorylated in response to transforming growth factor beta and are implicated in control of cell growth.

Yingling, Jonathan M.; Das, Pradeep; Savage, Cathy; Zhang, Ming; Padgett, Richard W.; Wang, Xiao Fan

doi:10.1073/pnas.93.17.8940

Cited by 139 publications

(88 citation statements)

References 27 publications

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“…While these authors reported that LEF-1 and Smad3 physically interacted and synergized to activate gene expression from the Xenopus homeobox twin gene promoter, they could not detect a cooperation of both proteins on LEF/TCF-specific reporters lacking Smad-binding elements (SBE), as seen in our study. However, also other studies reported a TGFb-activated and Smad3/Smad4-induced transcriptional response independent of an SBE (Yingling et al, 1996). Thus, the different results might be due to cell-type-specific expression or activation of different sets of signalling proteins in FosER and HepG2 cells.…”

Section: Cooperation Of Lef/tcf and Smad3/4 Proteinsmentioning

confidence: 51%

β-Catenin and TGFβ signalling cooperate to maintain a mesenchymal phenotype after FosER-induced epithelial to mesenchymal transition

et al. 2004

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Several signalling pathways contribute to the regulation of epithelial to mesenchymal transition (EMT), either during developmentally regulated processes or in cancer progression and metastasis. Induction of EMT in fully polarized mouse mammary epithelial cells (EpH4) by an inducible cfos estrogen receptor (FosER) oncoprotein involves loss of E-cadherin expression, nuclear translocation of b-catenin, and autocrine production of TGFb. Reporter assays demonstrate that both b-catenin/LEF-TCF-and TGFbSmad-dependent signalling activities are upregulated, probably coregulating mesenchymal-specific gene expression during EMT. Stable expression of E-cadherin in mesenchymal FosER cells decreased b-catenin activity and reduced cell proliferation. However, these cells still exhibited a defect in epithelial polarization and expressed E-cadherin/b-catenin complexes in the entire plasma membrane. On the other hand, inhibition of TGFb-Smad signalling in mesenchymal FosER cells induced flat, cobblestone-like clusters of cells, which relocalized bcatenin to the plasma membrane but still lacked detectable E-cadherin. Interestingly, inhibition of TGFb signalling in the E-cadherin-expressing mesenchymal FosER cells caused their reversion to a polarized epithelial phenotype, in which E-cadherin, b-catenin, and ZO-1 were localized at their correct lateral plasma membrane domains. These results demonstrate that loss of E-cadherin can contribute to increased LEF/TCF-b-catenin signalling, which in turn cooperates with autocrine TGFb signalling to maintain an undifferentiated mesenchymal phenotype.

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Section: Cooperation Of Lef/tcf and Smad3/4 Proteinsmentioning

confidence: 51%

β-Catenin and TGFβ signalling cooperate to maintain a mesenchymal phenotype after FosER-induced epithelial to mesenchymal transition

et al. 2004

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“…This, and the later observation that Smads have specific DNA binding activities, led to the conclusion that Smads function as transcription factors [12]. The link between activated TGF-β receptors and Smads was established with the key discovery that Smad is a substrate of the type I TGF-β receptor kinase and as a result the phosphorylated Smad concentrates in the nucleus [13][14][15]. Thus, being a signal-activated transcription factor, Smad is the central transducer of TGF-β signal.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Smad activities

2006

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expres

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TGF-β (Transforming Growth Factor-β) cytokines employ the Smad proteins as the intracellular mediator of signaling. Upon TGF-β stimulation, the cytoplasmic Smads become phosphorylated and consequently accumulate in the nucleus to regulate target gene expression. The cytoplasm-to-nucleus redistribution of Smads, as well as the ability of Smads to activate or repress gene transcription, is under multiple layers of regulation by factors not limited to TGF-β. With recent advance in the knowledge of regulatory factors impinged on Smads, we are beginning to understand the complexity in cellular responses to TGF-β.

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“…Signaling mediators downstream of the receptors for the TGFb superfamily were recently identi®ed in a variety of organisms, and termed`Smad' in vertebrates . While seven Smad genes have been reported in the literature thus far, they can be classi®ed into three types according to their functions, i.e., receptor-activated Smads (Smad1 and Smad5 for BMP; Smad2 and Smad3 for TGF-b and activin), co-Smad (Smad4) and anti-Smads (Smad6 and Smad7) Derynck et al, 1996;Eppert et al, 1996;Gra et al, 1996;Hahn et al, 1996;Hayashi et al, 1997;Hoodless et al, 1996;Lechleider et al, 1996;Liu et al, 1996;Riggins et al, 1996;Thomsen, 1996;Topper et al, 1997;Yingling et al, 1996;Zhang et al, 1996). Smad2 and Smad3, the receptor-activated, TGFb signaling Smads, are known to be highly homologous with regard to amino acid sequence and structural characteristics, and both have been found to mediate TGF-b and activin signals by forming heteromers with Smad4 (Eppert et al, 1996;Gra et al, 1996;Riggins et al, 1996;Wrana and Pawson, 1997;Zhang et al, 1996).…”

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confidence: 99%

Induction of apoptosis by Smad3 and down-regulation of Smad3 expression in response to TGF-β in human normal lung epithelial cells

et al. 1998

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Smad family members are essential intracellular signaling components of the transforming growth factor-beta (TGF-b) superfamily involved in a range of biological activities. Two highly homologous molecules, Smad2 and Smad3, have so far been identi®ed as receptor-activated Smads for TGF-b signaling and have become the focus of intensive studies. However, no de®nite di erences in regulation or function have been established between these TGF-b signaling molecules. In the present study, we show that the expression of Smad3, but not its close relative, Smad2, is down-regulated by TGF-b mediated signals themselves in human lung epithelial cells. This down-regulation of Smad3 by TGF-b treatment did not appear to result from shortening of the half-life of Smad3 mRNA. Constitutive expression of Smad3 in the presence of TGF-b induced apoptotic cell death, with an adverse e ect on the cell growth of human lung epithelial cells. Apoptotic cell death could also be induced by forced expression of Smad2 in the presence of TGF-b, but less e ciently than by that of Smad3. These ®ndings clearly de®ne the distinctions between Smad2 and Smad3 for the ®rst time in that a qualitative di erence was observed with regard to the regulation of their expression in response to TGF-b, while Smad2 and Smad3 appeared to have quantitatively di erent capabilities regarding the induction of apoptotic cell death in human lung epithelial cells.

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Mammalian dwarfins are phosphorylated in response to transforming growth factor beta and are implicated in control of cell growth.

Cited by 139 publications

References 27 publications

β-Catenin and TGFβ signalling cooperate to maintain a mesenchymal phenotype after FosER-induced epithelial to mesenchymal transition

β-Catenin and TGFβ signalling cooperate to maintain a mesenchymal phenotype after FosER-induced epithelial to mesenchymal transition

Regulation of Smad activities

Induction of apoptosis by Smad3 and down-regulation of Smad3 expression in response to TGF-β in human normal lung epithelial cells

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