Mutation analysis of the Smad3 gene in human ovarian cancers.

Wang, Dan; Kanuma, Tatsuya; Takama, Fumiko; Mizumuma, H.; Ibuki, Yoshito; Wake, Norio; Mogi, Akira; Shitara, Yoshinori; Hagiwara, Kaoru; Takenoshita, Seiichi

doi:10.3892/ijo.15.5.949

Cited by 19 publications

(19 citation statements)

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“…Modifications in TGFb signaling have been indicated in numerous types of cancers, including ovarian (Lynch et al, 1998;reviewed in Gold, 1999;Wang et al, 2000;Chen et al, 2001); however, we previously found that the TGFb signaling pathway was intact and functional in primary OC cells (Dunfield et al, 2002). Since OC cells produce and are exposed to bioactive TGFb (reviewed in Auersperg et al, 2001), inhibition of the antiproliferative effect of TGFb must exist to allow for the uncontrolled cellular proliferation of OC cells in vivo.…”

Section: Discussionmentioning

confidence: 97%

“…TbR1 mutations have been identified in chronic lymphocytic leukemia, gastric and prostate cancer. In OC, TbRI, TbRII and Smad2 mutations have been described; however, it is unknown whether these mutations alter protein function (Lynch et al, 1998;Wang et al, 2000;Chen et al, 2001). In contrast, we and others have previously shown that the TGFb signaling pathway is intact and functional in primary OC cells, and primary OC cells in culture stop growing in response to TGFb (Hurteau et al, 1994;Dunfield et al, 2002).…”

Section: Introductionmentioning

confidence: 88%

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Inhibition of the antiproliferative effect of TGFβ by EGF in primary human ovarian cancer cells

Dunfield

Nachtigal

2003

Oncogene

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 88%

Inhibition of the antiproliferative effect of TGFβ by EGF in primary human ovarian cancer cells

Dunfield

Nachtigal

2003

Oncogene

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“…The loss of Smad3 protects against fibrosis resulting from pathologic expression of TGF-␤, but confers susceptibility to emphysema by interfering with the normal physiologic (homeostatic) action of TGF-␤ in maintaining alveolar structure. This also suggests that in addition to the recognized association of susceptibility for emphysema to polymorphism in the MMP-12 gene, we should suspect a similar association might exist to polymorphism in the Smad3 gene, already known to be associated with the incidence of ovarian cancer (61,62).…”

Section: Fibrosis and Emphysema Represent Opposite Ends Of The Spectrmentioning

confidence: 99%

Smad3 Null Mice Develop Airspace Enlargement and Are Resistant to TGF-β-Mediated Pulmonary Fibrosis

Bonniaud

Kolb

Galt

et al. 2004

The Journal of Immunology

354

258

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Transforming growth factor-β1 plays a key role in the pathogenesis of pulmonary fibrosis, mediating extracellular matrix (ECM) gene expression through a series of intracellular signaling molecules, including Smad2 and Smad3. We show that Smad3 null mice (knockout (KO)) develop progressive age-related increases in the size of alveolar spaces, associated with high spontaneous presence of matrix metalloproteinases (MMP-9 and MMP-12) in the lung. Moreover, transient overexpression of active TGF-β1 in lungs, using adenoviral vector-mediated gene transfer, resulted in progressive pulmonary fibrosis in wild-type mice, whereas no fibrosis was seen in the lungs of Smad3 KO mice up to 28 days. Significantly higher levels of matrix components (procollagen 3A1, connective tissue growth factor) and antiproteinases (plasminogen activator inhibitor-1, tissue inhibitor of metalloproteinase-1) were detected in wild-type lungs 4 days after TGF-β1 administration, while no such changes were seen in KO lungs. These data suggest a pivotal role of the Smad3 pathway in ECM metabolism. Basal activity of the pathway is required to maintain alveolar integrity and ECM homeostasis, but excessive signaling through the pathway results in fibrosis characterized by inhibited degradation and enhanced ECM deposition. The Smad3 pathway is involved in pathogenic mechanisms mediating tissue destruction (lack of repair) and fibrogenesis (excessive repair).

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“…Indeed, TGFb RII was found mutated in colon and gastric carcinoma cells with microsatellite instability Myeroff et al, 1995). A frameshift mutation of RI was identified in about one-third of ovarian cancers examined (Wang et al, 2000). Mutations of Smad2 were found in colorectal carcinomas (Eppert et al, 1996) and mutations of Smad4/DPC4 were found in pancreatic carcinomas and juvenile polyposis Howe et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Autocrine TGFβ supports growth and survival of human breast cancer MDA-MB-231 cells

Lei

Bandyopadhyay

et al. 2002

Oncogene

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Using a cell model system established by ectopic expression of a soluble TGFb type III receptor (sRIII) containing the whole extracellular domain of the type III receptor in human breast cancer MDA-MB-231 cells, we observed that the expression of sRIII antagonized TGFb activity and inhibited both anchorage-dependent and anchorage-independent cell growth. Further studies revealed that sRIII expression induced apoptosis both in vitro and in vivo. Treatment with TGFb neutralizing antibodies or a recombinant human sRIII also induced apoptosis in the MDA-MB-231 parental cells, suggesting that the increased apoptosis after sRIII expression was specifically due to antagonization of autocrine TGFb signaling. Western blotting showed that sRIII clones had a higher PTEN expression level than the control cells did. Treatment with TGFb 1 decreased PTEN and inhibited apoptosis in sRIII cells to a level similar to that in the control cells. sRIII clones also showed a lower level of phosphorylated-Akt than the control cells, consistent with the inhibitory activity of PTEN on Akt activation. Treatment with LY294002, a specific inhibitor of Akt activator, phosphatidylinositol 3-kinase, also induced apoptosis in a dose dependent manner in the control cells. Our results suggest that autocrine TGFb signaling is necessary for the growth and survival of MDA-MB-231 cells.

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Mutation analysis of the Smad3 gene in human ovarian cancers.

Cited by 19 publications

References 0 publications

Inhibition of the antiproliferative effect of TGFβ by EGF in primary human ovarian cancer cells

Inhibition of the antiproliferative effect of TGFβ by EGF in primary human ovarian cancer cells

Smad3 Null Mice Develop Airspace Enlargement and Are Resistant to TGF-β-Mediated Pulmonary Fibrosis

Autocrine TGFβ supports growth and survival of human breast cancer MDA-MB-231 cells

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