The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta  signaling

Luo, Kunxin; Stroschein, Shannon L.; Wang, Wei; Chen, Dan; Martens, Eric; Zhou, Shi-Sheng; Zhou, Qiang

doi:10.1101/gad.13.17.2196

Cited by 441 publications

(414 citation statements)

References 59 publications

(101 reference statements)

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“…This ®nding is in agreement with Kim et al (1997), who showed that an equivalent mutation of R100T Smad4 in a carboxy-terminally truncated Drosophila Mad, resulted in a protein unable to bind to DNA. In addition, the lack of DNA binding of R100T Smad4 and P130S Smad4 mutants was recently shown by other research groups (Le Luo et al, 1999). Interestingly, combination of the R100T or P130S mutants described here with deletions of the carboxy-terminal 38 amino acids of Smad4, led to persistent loss of DNA binding or gain of weak DNA binding, respectively (Le .…”

Section: Smad4 With Missense Mutations Have Reduced Ability To Bind Dnasupporting

confidence: 67%

“…MH1 and MH2, which are separated by a proline-rich linker region of variable length, have distinct functions. The MH2 domain is important for homo-and heteromeric complex formation and for transcriptional activation and repression (Feng et al, 1998;Janknecht et al, 1998;Kawabata et al, 1998;Luo et al, 1999;Wotton et al, 1999). In addition, the MH2 domains of Smad2 and Smad3, but not Smad4, interact with type I receptors (Lo et al, 1998;MacõÂ as-Silva et al, 1996;Zhang et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

“…Smad2 is unable to bind directly to DNA because it contains an extra exon just N-terminal of the b-hairpin loop (Dennler et al, 1998;Yagi et al, 1999). SBE-like sequences have been identi®ed in the promoters of multiple TGF-b responsive genes, including plasminogen activator inhibitor-1 (PAI-1) (Dennler et al, 1998;Luo et al, 1999), junB (Jonk et al, 1998), type VII collagen (Vindevoghel et al, 1998) and the germline immunoglobulin Ia region (Hanai et al, 1999;Pardali et al, 2000a;Zhang and Derynck, 2000). Mutation of SBEs attenuate TGF-b inducibility.…”

Section: Introductionmentioning

confidence: 99%

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Functional consequences of tumorigenic missense mutations in the amino-terminal domain of Smad4

et al. 2000

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Smads, the intracellular e ectors of transforming growth factor-b (TGF-b) family members, are somatically mutated at high frequency in particular types of human cancers. Certain of these mutations a ect the Smad amino-terminal domain, which, in the case of Smad3 and Smad4, binds DNA. We investigated the functional consequences of four missense mutations in the Smad4 amino-terminal domain found in human tumors. The mutant proteins were found to have impaired abilities to bind DNA although they were fully capable of forming complexes with Smad3. All four Smad4 mutants showed decreased protein stability compared to wild-type Smad4. Two of the Smad4 mutants (G65V and P130S) were translocated to the nucleus and were capable of transactivating a Smad-dependent promoter in a liganddependent manner. In contrast, the L43S and R100T mutants were not translocated e ciently to the nucleus and consequently resulted in severely defective transcriptional responses to TGF-b. Moreover, we demonstrate here the critical importance of two basic residues in the b-hairpin loop of Smad3 or Smad4 for DNA binding, consistent with predictions from the Smad3 crystal structure. In addition, our results reveal that in the TGF-b-induced heteromeric signaling complex, loss of DNA binding of Smad4 can be compensated by Smad3, however, both Smad3 and Smad4 are needed for e cient DNA binding and signaling. In conclusion, mutations in the amino-terminal domain of Smad4, that are found in cancer, show loss of multiple functional properties which may contribute to tumorigenesis. Oncogene (2000) 19, 4396 ± 4404.

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Section: Smad4 With Missense Mutations Have Reduced Ability To Bind Dnasupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Functional consequences of tumorigenic missense mutations in the amino-terminal domain of Smad4

et al. 2000

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“…Ski has been shown to be involved in certain distinct signaling pathways including nuclear receptors (Dahl et al, 1998;Nomura et al, 1999;Ueki and Hayman, 2003b;Ritter et al, 2006), transforming growth factor-b (TGF-b) (Akiyoshi et al, 1999;Luo et al, 1999;Sun et al, 1999;Xu et al, 2000;Ueki and Hayman, 2003a) and tumor suppressors Tokitou et al, 1999;Khan et al, 2001) where Ski can act as a transcriptional corepressor. This is in part due to its direct and indirect interactions with histone deacetylase (HDAC) complexes including nuclear receptor-corepressor/silencing mediator for retinoid and thyroid hormone receptors (N-CoR/SMRT) and Sin3A corepressors Jepsen and Rosenfeld, 2002).…”

Section: Introductionmentioning

confidence: 99%

Ski can negatively regulates macrophage differentiation through its interaction with PU.1

2007

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“…Its gene product counts 728 amino acids and functions as a repressor of TGFb signaling by inhibiting R-SMAD (SMAD2-3) phosphorylation, hereby preventing assembly of the active heteromeric R-SMAD/SMAD4 complex and translocation to the nucleus. [13][14][15] Additionally, the SKI protein can recruit transcriptional corepressors including SNW1, N-CoR, and mSIN3 and forms a complex with histone deacetylases. 16,17 In vivo studies in Xenopus embryos, zebrafish, and mice have shown that SKI has a critical role in the development of neuronal and muscle cells or tissues.…”

Section: Introductionmentioning

confidence: 99%

The SMAD-binding domain of SKI: a hotspot for de novo mutations causing Shprintzen–Goldberg syndrome

et al. 2014

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Shprintzen-Goldberg syndrome (SGS) is a rare, systemic connective tissue disorder characterized by craniofacial, skeletal, and cardiovascular manifestations that show a significant overlap with the features observed in the Marfan (MFS) and Loeys-Dietz syndrome (LDS). A distinguishing observation in SGS patients is the presence of intellectual disability, although not all patients in this series present this finding. Recently, SGS was shown to be due to mutations in the SKI gene, encoding the oncoprotein SKI, a repressor of TGFb activity. Here, we report eight recurrent and three novel SKI mutations in eleven SGS patients. All were heterozygous missense mutations located in the R-SMAD binding domain, except for one novel in-frame deletion affecting the DHD domain. Adding our new findings to the existing data clearly reveals a mutational hotspot, with 73% (24 out of 33) of the hitherto described unrelated patients having mutations in a stretch of five SKI residues (from p.(Ser31) to p. (Pro35)). This implicates that the initial molecular testing could be focused on mutation analysis of the first half of exon 1 of SKI. As the majority of the known mutations are located in the R-SMAD binding domain of SKI, our study further emphasizes the importance of TGFb signaling in the pathogenesis of SGS.

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The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling

Cited by 441 publications

References 59 publications

Functional consequences of tumorigenic missense mutations in the amino-terminal domain of Smad4

Functional consequences of tumorigenic missense mutations in the amino-terminal domain of Smad4

Ski can negatively regulates macrophage differentiation through its interaction with PU.1

The SMAD-binding domain of SKI: a hotspot for de novo mutations causing Shprintzen–Goldberg syndrome

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