The Transforming Activity of Ski and SnoN Is Dependent on Their Ability to Repress the Activity of Smad Proteins

He, Jun; Tegen, Sarah B.; Krawitz, Ariel R.; Martin, G S; Luo, Kunxin

doi:10.1074/jbc.m304016200

Cited by 99 publications

(108 citation statements)

References 60 publications

(80 reference statements)

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“…Although phosphorylation of R-Smads and accumulation of phosphorylated Smads in the nucleus are typical indicators of TGF-b and BMP stimulation, it is known that transcriptional corepressors, including c-Ski and SnoN, are overexpressed in some cancer cells, in which they inhibit TGF-b and BMP signaling through interactions with Smad complexes (He et al, 2003;Fukuchi et al, 2004). To study whether Smad-dependent transcriptional pathways were active in the bone metastasis, we used a functional imaging system using a xenograft model.…”

Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway

et al. 2008

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Transforming growth factor (TGF)-b is known to promote tumor invasion and metastasis. Although bone morphogenetic proteins (BMPs), members of the TGF-b family, are expressed in a variety of human carcinoma cell lines, their roles in tumor progression have not been fully clarified. In this study, we sought to determine the roles of BMPs in the progression of breast cancer bone metastasis using human breast cancer samples and a mouse xenograft model. Immunohistochemical analysis of samples from breast cancer patients as well as a mouse xenograft model of MDA-231-D, highly metastatic human breast cancer cells, revealed phospho-Smad2 and phospho-Smad1/5/8 staining in the nuclei of cancer cells in primary tumor and/ or bone metastasis. Using a functional in vivo bioluminescence imaging system, we showed that TGF-b-and BMPinduced transcriptional pathways are active in bone metastatic lesions in vivo. In addition, both TGF-b3 and BMP-2 promoted the motility and invasiveness of the MDA-231-D cells in vitro. Moreover, expression of dominant-negative receptors for TGF-b and/or BMPs in the MDA-231-D cells inhibited invasiveness in vitro and bone metastasis in the xenograft model. These results suggest that BMPs as well as TGF-b promote invasion and bone metastasis of breast cancer.

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Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway

et al. 2008

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“…The R-Smad binding region has recently been reported to be located between amino acid residues 16 and 40 (Qin et al, 2002) or the N-terminal 23 amino acid residues (Wu et al, 2002) of c-Ski. Although Smad2/3 also binds the middle region of c-Ski (amino acid residues 335-490 or 241-441), the affinity of the middle region appears to be lower than that of the N-terminal region (Akiyoshi et al, 1999;He et al, 2003;our unpublished observation). We thus constructed a truncated mutant lacking the N-terminal 40 amino acid residues (⌬40) as well as a double mutant with ⌬40 and ARPG insertion and confirmed that the ⌬40 mutation caused loss of R-Smad binding.…”

Section: Lack Of Smad4 Binding Confers Tgf-␤/activin Selectivity To Cmentioning

confidence: 99%

“…Although the oncogenic mechanism of v-Ski is not fully understood, suppression of TGF-␤-induced growth inhibition is thought to be a part of the oncogenic properties of Ski proteins (He et al, 2003). v-Ski has a truncated structure in both the N-and C-termini of c-Ski; v-Ski lacks a 23-amino acid region from its N-terminus, and a 292-amino acid region from its C-terminus .…”

Section: Molecular Basis For the Loss Of Transforming Activity Of V-smentioning

confidence: 99%

“…v-Ski has a truncated structure in both the N-and C-termini of c-Ski; v-Ski lacks a 23-amino acid region from its N-terminus, and a 292-amino acid region from its C-terminus . Because the truncated region in the N-terminus constitutes the R-Smad binding site, v-Ski is unable to interact with R-Smads (He et al, 2003). The C-terminal truncated region includes one of the mSin3A binding regions (Nomura et al, 1999).…”

Section: Molecular Basis For the Loss Of Transforming Activity Of V-smentioning

confidence: 99%

“…High levels of expression of c-Ski were reported in several tumor cell lines (Nomura et al, 1989;Fumagalli et al, 1993) and in melanomas in vivo (Reed et al, 2001). Inhibition of TGF-␤ signaling is thus regarded as a part of the mechanism of oncogenesis by Ski proteins (He et al, 2003). c-Ski recruits HDACs via N-CoR as well as mSin3A and represses transcriptional activities of Smads.…”

Section: Introductionmentioning

confidence: 99%

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Interaction with Smad4 Is Indispensable for Suppression of BMP Signaling by c-Ski

Takeda

Mizuide

Oka³

et al. 2004

MBoC

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c-Ski is a transcriptional corepressor that interacts strongly with Smad2, Smad3, and Smad4 but only weakly with Smad1 and Smad5. Through binding to Smad proteins, c-Ski suppresses signaling of transforming growth factor-␤ (TGF-␤) as well as bone morphogenetic proteins (BMPs). In the present study, we found that a mutant of c-Ski, termed c-Ski (ARPG) inhibited TGF-␤/activin signaling but not BMP signaling. Selectivity was confirmed in luciferase reporter assays and by determination of cellular responses in mammalian cells (BMP-induced osteoblastic differentiation of C2C12 cells and TGF-␤-induced epithelial-to-mesenchymal transdifferentiation of NMuMG cells) and Xenopus embryos. The ARPG mutant recruited histone deacetylases 1 (HDAC1) to the Smad3-Smad4 complex but not to the Smad1/5-Smad4 complex. c-Ski (ARPG) was unable to interact with Smad4, and the selective loss of suppression of BMP signaling by c-Ski (ARPG) was attributed to the lack of Smad4 binding. We also found that c-Ski interacted with Smad3 or Smad4 without disrupting Smad3-Smad4 heteromer formation. c-Ski (ARPG) would be useful for selectively suppressing TGF-␤/activin signaling. INTRODUCTIONCytokines of the transforming growth factor-␤ (TGF-␤) superfamily are multifunctional proteins that regulate growth, differentiation, apoptosis, and morphogenesis of a wide variety of cell types. TGF-␤ and related factors bind to two different types of serine/threonine kinase receptors, termed type I and type II (Derynck et al., 1998;Attisano and Wrana, 2000;Shi and Massagué, 2003). Type I receptor is activated by type II receptor upon ligand binding and transduces signals into cytoplasm through phosphorylation of receptorregulated Smads (R-Smads). Phosphorylated R-Smads interact with Co-Smad (Smad4) and translocate into the nucleus. Nuclear Smad complexes regulate transcription of target genes in cooperation with transcriptional activators/repressors as well as with coactivators/corepressors . Of the eight different mammalian Smad proteins, Smad1, Smad5, and Smad8 are R-Smads activated by BMP family members, whereas Smad2 and Smad3 are R-Smads activated by TGF-␤ and activin.Transcription of target genes by TGF-␤ is upregulated by binding of Smads to transcriptional coactivators, including p300 and CBP, which induce acetylation of histones and loosen chromatin structure (Massagué and Chen, 2000;Miyazono et al., 2001). In contrast, transcriptional corepressors, including TGIF, c-Ski, and SnoN, physically interact with Smads, and repress TGF-␤ signaling through recruitment of histone deacetylases (HDACs) (Massagué and Chen, 2000;Liu et al., 2001).c-Ski was originally identified as a cellular counterpart of a retroviral oncogene product, v-Ski (Li et al., 1986). c-Ski physically interacts with Smad2, Smad3, and Smad4, thus antagonizing signal transduction in the TGF-␤ pathway (Akiyoshi et al., 1999;Luo et al., 1999;Sun et al., 1999;Xu et al., 2000). Overexpression of c-Ski abolished TGF-␤-induced growth inhibition (Luo et al., 1999;Sun et al., 1999;Xu et al., 200...

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Involvement of the constitutive complex formation of c‐Ski/SnoN with smads in the impaired negative feedback regulation of transforming growth factor β signaling in scleroderma fibroblasts

Jinnin¹,

Ihn²,

Mimura³

et al. 2007

Arthritis & Rheumatism

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Objective. The principal effect of transforming growth factor ␤1 (TGF␤1) on mesenchymal cells is its stimulation of extracellular matrix synthesis. Previous reports indicated the significance of the autocrine TGF␤ loop in the pathogenesis of scleroderma. The aim of this study was to examine c-Ski and SnoN, principal molecules in the negative regulation of TGF␤ signaling, to further understand the autocrine TGF␤ loop in scleroderma.Methods. Levels of expression of c-Ski/SnoN on cultured normal and scleroderma fibroblasts were determined by Western blotting, Northern blotting, and immunohistochemical staining. To determine the protein-protein interaction between c-Ski/SnoN, Smads, and p300, immunoprecipitation was performed. A transient transfection assay was performed to measure promoter activity of the ␣2(I) collagen gene and the 3TP-Lux plasmid construct.Results. Scleroderma fibroblasts exhibited increased c-Ski/SnoN levels compared with normal fibroblasts, both in vivo and in vitro. Although c-Ski/SnoN constitutively formed a complex with Smads by immunoprecipitation, the inhibitory effect of c-Ski/SnoN on the promoter activity of human ␣2(I) collagen and 3TP-Lux was impaired in scleroderma fibroblasts. Immunoprecipitation analyses also revealed that overexpressed c-Ski/SnoN could not compete with p300 in these cells.Conclusion. These results indicate that impaired competition with p300 is the possible cause of dysfunction of c-Ski/SnoN in scleroderma fibroblasts and that this might contribute to maintenance of the autocrine TGF␤ loop in this disease.

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The Transforming Activity of Ski and SnoN Is Dependent on Their Ability to Repress the Activity of Smad Proteins

Cited by 99 publications

References 60 publications

Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway

Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway

Interaction with Smad4 Is Indispensable for Suppression of BMP Signaling by c-Ski

Involvement of the constitutive complex formation of c‐Ski/SnoN with smads in the impaired negative feedback regulation of transforming growth factor β signaling in scleroderma fibroblasts

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