Isolation of genes differentially expressed in human primary myoblasts and embryonal rhabdomyosarcoma

Genini, Michele; Schwalbe, P; Scholl, Florence A.; Schäfer, Beat W.

doi:10.1002/(sici)1097-0215(19960516)66:4<571::aid-ijc24>3.3.co;2-v

Cited by 17 publications

(16 citation statements)

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“…TGF-b acts as a tumor suppressor by inhibiting cellular proliferation or by promoting cellular differentiation or apoptosis (Epstein, 2000). Although the role of big-h3 in tumors has not been extensively studied, it has been reported to be downregulated in mesenchymal tumor cells (Schenker and Trueb, 1998) and rhabdomyosarcoma (Genini et al, 1996). Our observations suggest that the TGFb-induced-big-h3 could be a mechanism mediating TGF-b-mediated tumor suppression and that it may act as a tumor suppressor.…”

Section: Discussionmentioning

confidence: 63%

RGD peptides released from βig-h3, a TGF-β-induced cell-adhesive molecule, mediate apoptosis

Kim

Jeong

et al. 2003

Oncogene

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big-h3 is a transforming growth factor-b (TGF-b)-induced cell-adhesive molecule and has an RGD sequence at its Cterminus. A previous report suggested that big-h3 normally undergoes carboxy-terminal processing that results in the loss of the RGD sequence. RGD peptides appear to play various roles in cell function. Here we show that the RGD peptides released from big-h3 may facilitate TGF-b-induced apoptosis. We found that carboxy-terminal cleavage of big-h3 occurred after its secretion, and that overexpression of the wild-type big-h3 induced apoptosis, unlike the C-terminal deleted but RGDcontaining mutant big-h3, which is resistant to C-terminal processing. The big-h3-induced apoptosis was abolished by either deletion of the RGD sequence or mutation of RGD to RAE. Synthetic peptides of ERGDEL and GRGDSP derived from big-h3 and fibronectin, respectively, also induced apoptosis, unlike ERGEEL and GRGESP. Culture supernatants of cells overexpressing big-h3 filtered to isolate molecules smaller than 3 kDa also induced apoptosis. A fusion protein composed of the N-terminal 100 amino acids of fibronectin and the RGDcontaining C-terminal part of big-h3 was also subjected to C-terminal cleavage and overexpression resulted in apoptosis. The anti-big-h3 antibody blocks TGF-binduced apoptosis. Thus, big-h3 may be important in regulating cell apoptosis by providing soluble RGD peptides.

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Section: Discussionmentioning

confidence: 63%

RGD peptides released from βig-h3, a TGF-β-induced cell-adhesive molecule, mediate apoptosis

Kim

Jeong

et al. 2003

Oncogene

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“…Altered expression of a series of genes that controlled cellular growth and differentiation between these two cell models was found (Zhao et al, 2001), with Betaig-h3 gene notably downregulated in tumour cells, a finding that was further confirmed in five tumour cell lines by Northern blot. Previous studies have shown that Betaig-h3 gene is significantly reduced in embryonal rhabdomyosarcoma cell lines and mesenchymal tumours (Genini et al, 1996;Schenker and Trueb, 1998), suggesting that Betaig-h3 may have an important role in human cancer. Although overexpression of this gene in CHO fibroblast cells leads to a marked decrease in their ability to form tumour in nude mice (Skonier et al, 1994), little is known about its regulation in tumour progression of human tissues.…”

Section: Discussionmentioning

confidence: 96%

Overexpression of Betaig-h3 gene downregulates integrin α5β1 and suppresses tumorigenicity in radiation-induced tumorigenic human bronchial epithelial cells

2002

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{Interaction between cell and extracellular matrix plays a crucial role in tumour invasion and metastasis. Using an immortalised human bronchial epithelial (BEP2D) cell model, the study here shows that expression of Betaig-h3 gene, which encodes a secreted adhesion molecule induced by transforming growth factor-b, is markedly decreased in several independently generated, radiation-induced tumour cell lines (TL1 -TL5) relative to parental BEP2D cells. Transfection of Betaig-h3 gene into tumour cells resulted in a significant reduction in tumour growth. While integrin receptor a5b1 was overexpressed in tumour cells, its expression was corrected to the level found in control BEP2D cells after Betaig-h3 transfection. These data suggest that Betaig-h3 gene is involved in tumour progression by regulating integrin receptor a5b1. The findings provide strong evidence that the Betaig-h3 gene has tumour suppressor function in human BEP2D cell model and suggest a potential target for interventional therapy.

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“…RH30 as well as 293T cells were purchased from the American Type Culture collection (ATCC, LGC Promochem, Molsheim Cedex, France). A33 and B6M myoblasts were established in our laboratories (Genini et al, 1996). SkM1 and SkM2 myoblasts were purchased from Promocell (Allschwil, Switzerland).…”

Section: Cell Lines and Pharmacologic Inhibitors Alveolar Rhabdomyosmentioning

confidence: 99%

p21 Downregulation is an important component of PAX3/FKHR oncogenicity and its reactivation by HDAC inhibitors enhances combination treatment

et al. 2010

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A number of drugs developed against cancer-specific molecular targets have been shown to offer survival benefits alone or in combination with standard treatments, especially for those cases where tumor pathogenesis is dominated by a single molecular abnormality. One example for such a tumor type is alveolar rhabdomyosarcoma (aRMS) which is characterized by a specific translocation creating the oncogenic PAX3/FKHR transcription factor, believed to be the molecular basis of the disease.Recently, we were able to demonstrate that the small molecule inhibitor PKC412 (midostaurin) exhibits strong antitumor activity against aRMS by reducing the transcriptional activity of PAX3/FKHR.Here, we screened for combination strategies that are superior to PKC412-only treatment and found that the combination of PKC412 with histone deacetylase (HDAC) inhibitors like valproic acid (VPA) synergistically induced apoptosis resulting in suppressed aRMS tumor growth in vivo.We provide evidence that the antitumor effect upon combination treatment is achieved by VPAinduced reactivation of p21 which is downregulated in aRMS cells via destabilization of the transcriptional regulator EGR1 by PAX3/FKHR. Our study highlights a possible mechanism behind the increased efficacy and indicates that different arms of PAX3/FKHR oncogenicity can be exploited therapeutically by the specific combination of drugs to increase their therapeutic potential.

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Isolation of genes differentially expressed in human primary myoblasts and embryonal rhabdomyosarcoma

Abstract: o 1996 Wiley-Liss, Inc.

Cited by 17 publications

References 0 publications

RGD peptides released from βig-h3, a TGF-β-induced cell-adhesive molecule, mediate apoptosis

RGD peptides released from βig-h3, a TGF-β-induced cell-adhesive molecule, mediate apoptosis

Overexpression of Betaig-h3 gene downregulates integrin α5β1 and suppresses tumorigenicity in radiation-induced tumorigenic human bronchial epithelial cells

p21 Downregulation is an important component of PAX3/FKHR oncogenicity and its reactivation by HDAC inhibitors enhances combination treatment

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