Increased susceptibility to tumorigenesis of ski-deficient heterozygous mice

Transforming growth factor‐β (TGF‐β) is a potent growth inhibitor of most types of cells; therefore, perturbations of TGF‐β signaling are believed to result in progression of various tumors. On the other hand, TGF‐β has been shown to act as an oncogenic cyto‐kine through induction of extracellular matrices, angiogenesis, and immune suppression. A wide variety of effects of TGF‐p are mediated by physical interaction of signal transducer Smad proteins with various transcription factors. Among these, Runx3 plays a pivotal role in prevention of gastric cancer. TGF‐β signaling is regulated by various mechanisms in the cytoplasm and nucleus. Inhibitory Smads (l‐Smads) repress TGF‐β signaling mainly by interacting with activated TGF‐β receptors. Smad ubiquitin regulatory factors (Smurfs) play important roles in facilitating the inhibitory signals induced by l‐Smads. In addition, the transcrip‐tional co‐repressors c‐Ski and SnoN interact with Smads, and repress transcription induced by TGF‐β. Abnormalities of these regulators of TGF‐β signaling may thus participate in the progression of various tumors. (Cancer Sci 2003; 94: 230–234)

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“…48,49) The SnoN +/− mice develop lymphomas at low frequency. Thus, c-Ski and SnoN act as tumor suppressors in certain cells.…”

Section: Transcriptional Co-repressors C-ski and Snonmentioning

confidence: 99%

Regulation of TGF‐β signaling and its roles in progression of tumors

2003

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“…Recently, several in-frame mutations in exon 1 of Ski (the R-Smad binding region) have been identified as the main cause of the human ShprintzenGoldberg syndrome, and increased TGF-␤ signaling has been associated with this pathogenesis (34). Furthermore, Ski knockout mice exhibit embryonic lethality, and heterozygous mice show a high sensitivity to developing cancer (35,36). By contrast, transgenic mice overexpressing Ski protein exhibit increased muscle mass (17).…”

Section: Discussionmentioning

confidence: 99%

Novel Regulation of Ski Protein Stability and Endosomal Sorting by Actin Cytoskeleton Dynamics in Hepatocytes

Vázquez‐Victorio

Caligaris

Valle-Espinosa

et al. 2015

Journal of Biological Chemistry

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“…Histological Analysis-Deparaffinized sections of C57BL/6 mouse liver were stained with an anti-C184M polyclonal antibody (1:50) or a mixture of the anti-Ski monoclonal antibodies 1-1, 9-1, 11-1, and 16-1 (1:50) as described previously (31).…”

Section: Methodsmentioning

confidence: 99%

The Ski-binding Protein C184M Negatively Regulates Tumor Growth Factor-β Signaling by Sequestering the Smad Proteins in the Cytoplasm

Kokura

Kim

Shinagawa

et al. 2003

Journal of Biological Chemistry

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Ski is a transcriptional co-repressor and is involved in the negative regulation of tumor growth factor-␤ (TGF-␤) signaling. To understand more fully the role of Ski in TGF-␤ signaling, we searched for novel Ski-interacting proteins. The identified C184M protein consists of 189 amino acids and contains the leucine-rich region. An association between Ski and C184M involving the leucine-rich region of C184M and the C-terminal coiledcoil motif of Ski was confirmed by glutathione S-transferase pull-down and immunoprecipitation assays. The C184M protein is located in the cytosol, and the C184M and Ski signals are co-localized in the cytoplasm when C184M was co-expressed with Ski in CV-1 cells. The cytoplasmic C184M-Ski complex inhibited the nuclear translocation of Smad2. Consistent with this, the activity of promoter containing the Smad-binding sites was repressed by C184M, and the TGF-␤-induced growth inhibition of mink lung Mv1Lu cells was attenuated by the ectopic expression of C184M. Thus, C184M inhibits TGF-␤ signaling in concert with Ski. In hepatocytes, which express significant levels of C184M, the Ski signals were found only in the cytoplasm, supporting the notion that C184M forms a complex with Ski in the cytosol.

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Increased susceptibility to tumorigenesis of ski-deficient heterozygous mice

Cited by 81 publications

References 69 publications

Regulation of TGF‐β signaling and its roles in progression of tumors

Regulation of TGF‐β signaling and its roles in progression of tumors

Novel Regulation of Ski Protein Stability and Endosomal Sorting by Actin Cytoskeleton Dynamics in Hepatocytes

The Ski-binding Protein C184M Negatively Regulates Tumor Growth Factor-β Signaling by Sequestering the Smad Proteins in the Cytoplasm

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