A TGF-?-inducible cell adhesion molecule, ?ig-h3, is downregulated in melorheostosis and involved in osteogenesis

Kim, Jung-Eun; Kim, Eui Hyun; Han, EunHee; Park, Rang-Woon; Park, Il-Hyung; Jun, Soo Han; Kim, Jung‐Chul; Young, Marian F.; Kim, In‐San

doi:10.1002/(sici)1097-4644(20000501)77:2<169::aid-jcb1>3.0.co;2-l

Cited by 111 publications

(63 citation statements)

References 27 publications

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“…The big-h3 cDNAs lacking the Cterminal 30 and 44 amino acids were subcloned into the same vector, yielding the pMycb-DC30 and -DC44 constructs, respectively. The substitution mutant of pMycb-WT, where RGD was altered into RAE, was generated by a two-step PCR as described previously (Kim et al, 2000a). The 1.13 kb Nterminal fragment of human FN corresponding to amino acids 1-100 was subcloned into the KpnI and SphI sites of pMycb-WT, thereby producing a fusion protein consisting of the FN N-terminal fragment fused to a C-terminal fragment of big-h3 corresponding to amino acids 518-683.…”

Section: Dna Constructsmentioning

confidence: 99%

“…The protein contains an RGD motif and four internal repeat domains that have highly conserved sequences also found in various secretory and membrane proteins from several species, including mammals, insects, sea urchins, plants, yeast, and bacteria (Kawamoto et al, 1998). A number of studies have suggested that big-h3 is involved in cell growth (Skonier et al, 1994), cell differentiation (Dieudonne et al, 1999;Kim et al, 2000a), wound healing (Rawe et al, 1997), and cell adhesion (LeBaron et al, 1995;Ohno et al, 1999). Although the underlying mechanisms driving these effects have not been defined, we recently reported that big-h3 may mediate cell adhesion by interacting with the a3b1 integrin through two motifs residing within the 2nd and 4th repeat domains (Kim et al, 2000b).…”

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confidence: 99%

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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: Dna Constructsmentioning

confidence: 99%

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confidence: 99%

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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“…BigH3 has been immunohistochemically found in human tissues such as corneal, skin, lung, bone, bladder, and kidney (26). In addition, BigH3 is involved in certain human diseases such as corneal dystrophies (27,28), melorheostosis, osteogenesis (29), diabetic angiopathy, atherothrombosis and restenosis (30).…”

Section: Introductionmentioning

confidence: 99%

BigH3 protein expression as a marker for breast cancer

Calaf

Echiburú-Chau²,

Zhao³

et al. 2008

Int J Mol Med

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Abstract. The current hypothesis of tumorigenesis in humans suggests that cancer cells acquire their hallmarks of malignancy through the accumulation of advantageous gene activation and inactivation events over long periods of time. For breast cancer development, this multistep process may manifest itself as a sequence of pathologically defined stages. It is widely held that breast cancer originates at the premalignant stage of atypical ductal hyperplasia, progresses to the preinvasive stage of ductal carcinoma in situ, and culminates in the potentially lethal stage of invasive ductal carcinoma. Tumor grade has been a highly valuable prognostic factor for breast cancer, and high-grade ductal carcinoma in situ lesions are associated with poor clinical outcome. The aim of this work was to investigate the BigH3 protein expression changes associated with various stages of breast cancer progression in comparison to benign specimens using tissue microarray technology. Pathological characteristics of breast tissues ranged from benign lesions to breast cancers either of lobular or ductal carcinomas in origin, and included in situ ductal carcinomas, lobular carcinomas, infiltrating ductal carcinomas, carcinomas, scirrhous carcinomas, adenocarcinomas and infiltrating colloid carcinomas. BigH3 protein expression was analyzed by immunohistochemistry in 192 cases of breast tumors. Results indicated a decrease in BigH3 protein expression from benign tissues to in situ ductal carcinoma, lobular carcinoma, infiltrating ductal carcinomas, carcinomas, scirrhous carcinoma, adenocarcinomas to infiltrating colloid carcinomas. We observed that the benign tissue had a 23-fold increase in BigH3 protein expression compared to the infiltrating colloid carcinoma which was the most malignant tissue analyzed. In summary, these studies confirmed the suppressor effect of the BigH3 gene expressed as protein expression in those processes related to the progression of breast tumorigenesis. We conclude that this protein can be used as a marker for breast cancer progression.

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“…Although transfection of Betaig-h3 gene into CHO (Chinese Hamster Ovary) fibroblasts markedly reduces their ability to form tumours in nude mice (Skonier et al, 1994), its expression as well as regulation in human tumour has not been examined until now. There is evidence that mutations or altered expression of this gene are involved in corneal dystrophy and osteogenesis in human (Bron, 2000;Kim et al, 2000a). In addition, Betaig-h3 protein is a component of ECM in lung, bladder and skin (LeBaron et al, 1995;Billings et al, 2000a,b), which promotes adhesion and the spreading of dermal fibroblasts in vitro and mediates cell adhesion by interacting with a3b1 integrin in human corneal epithelial cells (Billings et al, 2000b;Kim et al, 2000b).…”

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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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A TGF-?-inducible cell adhesion molecule, ?ig-h3, is downregulated in melorheostosis and involved in osteogenesis

Cited by 111 publications

References 27 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

BigH3 protein expression as a marker for breast cancer

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

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