Differential Inhibition of Smad6 and Smad7 on Bone Morphogenetic Protein- and Activin-mediated Growth Arrest and Apoptosis in B Cells

Ishisaki, Akira; Kikkawa, Yamato; Hashimoto, Shinichi; Nakao, Akihiro; Tamaki, Kiyoshi; Nonaka, Koji; Dijke, Peter ten; Sugino, Hiromu; Nishihara, Tatsuji

doi:10.1074/jbc.274.19.13637

Cited by 209 publications

(174 citation statements)

References 43 publications

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“…One way by which this occurs is through the action of inhibitory (I-) Smads (Fig. 1) CELL PROLIFERATION CONTROL BY SMADS (Hayashi et al, 1997;Imamura et al, 1997;Nakao et al, 1997;Hata et al, 1998a;Ishisaki et al, 1998Ishisaki et al, , 1999Souchelnytskyi et al, 1998;Lebrun et al, 1999). Whereas Smad7 acts as a general inhibitor of TGF-b family member signaling pathway, Smad6 preferentially blocks BMP signaling Ishisaki et al, 1999).…”

Section: Negative Regulation Of R-and Co-smadsmentioning

confidence: 99%

“…1) CELL PROLIFERATION CONTROL BY SMADS (Hayashi et al, 1997;Imamura et al, 1997;Nakao et al, 1997;Hata et al, 1998a;Ishisaki et al, 1998Ishisaki et al, , 1999Souchelnytskyi et al, 1998;Lebrun et al, 1999). Whereas Smad7 acts as a general inhibitor of TGF-b family member signaling pathway, Smad6 preferentially blocks BMP signaling Ishisaki et al, 1999). The ®rst described mechanism for I-Smads antagonism was through their competition with R-Smads for the interaction with the activated type I receptor (Hayashi et al, 1997;Imamura et al, 1997;Nakao et al, 1997;Souchelnytskyi et al, 1998).…”

Section: Negative Regulation Of R-and Co-smadsmentioning

confidence: 99%

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Regulation of cell proliferation by Smad proteins

Dijke

Goumans

Itoh

2002

Journal Cellular Physiology

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399

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Transforming growth factor-b (TGF-b) family members which include TGF-bs, activins, and bone morphogenetic proteins (BMPs) regulate a broad spectrum of biological responses on a large variety of cell types. TGF-b family members initiate their cellular responses by binding to distinct receptors with intrinsic serine/ threonine kinase activity and activation of speci®c downstream intracellular effectors termed Smad proteins. Smads relay the signal from the cell membrane to the nucleus, where they affect the transcription of target genes. Smad activation, subcellular distribution, and stability have been found to be intricately regulated and a broad array of transcription factors have been identi®ed as Smad partners. Important activities of TGF-b are its potent anti-mitogenic and pro-apoptotic effects that, at least in part, are mediated via Smad proteins. Escape from TGF-b/ Smad-induced growth inhibition and apoptosis is frequently observed in tumors. Certain Smads have been found to be mutated in speci®c types of cancer and gene ablation of particular Smads in mice has revealed increased rate of tumorigenesis. In late stage tumors, TGF-b has been shown to function as a tumor promoter. TGFb can stimulate the de-differentiation of epithelial cells to malignant invasive and metastatic ®broblastic cells. Interestingly, TGF-b may mediate these effects directly on tumor cells via subverted Smad-dependent and/or Smad-independent pathways.

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Section: Negative Regulation Of R-and Co-smadsmentioning

confidence: 99%

Section: Negative Regulation Of R-and Co-smadsmentioning

confidence: 99%

Regulation of cell proliferation by Smad proteins

Dijke

Goumans

Itoh

2002

Journal Cellular Physiology

Self Cite

399

278

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“…While both Smads 6 and 7 inhibit Smad-mediated signaling events, Smad6 ~3,301. appears more specific for BMP related signaling [15,19]. Smad6 mediated inhibition has been shown to be important in a number of cells and tissues, playing a fundamental role in processes such as development [ 10,321, apoptosis [19] and tissue repair [33].…”

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confidence: 99%

Smad6 is induced by BMP‐2 and modulates chondrocyte differentiation

Ionescu

Schwarz

et al. 2003

Journal Orthopaedic Research

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BMPs regulate cartilage differentiation and have been approved for clinical use as stimulators of bone repair. BMP signaling is complex and there are multiple potential points of regulation, including modulation of Smad signaling, which is inhibited by both Smad6 and Smad7. In the current manuscript we assessed the expression and biological function of Smad6 during chondrocyte differentiation. We found that the induction of chondrocyte differentiation by BMP-2 in chicken sternal embryonic chondrocytes was accompanied by a marked increase in Smad6 mRNA and protein levels. A morpholino antisense oligonucleotide cornplementary to Smad6 reduced the expression of Smad6 protein and enhanced the stimulatory effect of BMP-2 on both colX and alkaline phosphatase activity. In contrast, over-expression of Smad6 blocked BMP-2 mediated induction of the type X collagen promoter, b2-640 Luc. Therefore, expression studies as well as gain and loss of function experiments suggest that Smad6 participates in an important negative feedback loop whereby BMP-2 mediated effects on chondrocyte differentiation are reduced by induction of Smad6. Additional studies are required to determine the extent to which this pathway participates in pathologic processes involving cartilage.

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“…[14][15][16] The antiproliferative activity of TGFb, Acts and BMPs in lymphocytes is well established. 17,18 However, TGFb family members modulate many other B-and T-cell responses like cell adhesion, apoptosis or cytokine secretion. [19][20][21] At the cell surface, TGFb, Act or BMPs bind to a type II receptor, which recruits and phosphorylates a type I receptor to form a type I/type II receptor complex.…”

Section: Introductionmentioning

confidence: 99%

TGFβ-mediated activation of Smad1 in B-cell non-Hodgkin's lymphoma and effect on cell proliferation

et al. 2004

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We have previously reported an overexpression of Smad1 in follicular lymphoma (FL) cells, which are characterized by the t(14;18) bcl2/IgH translocation. Smad1 is commonly involved in bone morphogenetic protein but not in tumor-transforming growth factor beta (TGFb) signaling pathways. This study focuses on Smad1 signaling pathway in non-Hodgkin lymphoma cells including follicular or large-cell lymphoma cells. Our results support the notion that phosphorylation of Smad1 is mediated by TGFb present in the microenvironment and occurs in FL in vivo. Using an in vitro coculture system mimicking interactions between stroma cells and FL cells, we found that both the cell partners release TGFb at a sufficient concentration to activate Smad pathways in the malignant cells. This Smad1 activation involves TGFbRII but not ALK-1 receptors, and does not compete with the Smad2 pathway. Moreover, proliferation assays performed on lymphoma cells expressing wild-type or mutated Smad1, or in which endogenous Smad1 level was decreased by gene silencing, strongly supported that overexpression and activation of Smad1 modifies the biological response of lymphoma B cells to TGFb family members. This work opens new insights into aberrant Smad pathways and their pathophysiological role in FL and in other non-Hodgkin lymphomas.

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Differential Inhibition of Smad6 and Smad7 on Bone Morphogenetic Protein- and Activin-mediated Growth Arrest and Apoptosis in B Cells

Cited by 209 publications

References 43 publications

Regulation of cell proliferation by Smad proteins

Regulation of cell proliferation by Smad proteins

Smad6 is induced by BMP‐2 and modulates chondrocyte differentiation

TGFβ-mediated activation of Smad1 in B-cell non-Hodgkin's lymphoma and effect on cell proliferation

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