Integrins.

Ruoslahti, Erkki

doi:10.1172/jci114957

Cited by 1,495 publications

(830 citation statements)

References 39 publications

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“…hesion to collagen IV and laminin E8 substrates was insensitive to inhibition by both peptides, with I&, values distinctly above 500,~M. This is in accordance with previous data [21, 22,26] showing that these adhesions are mediated by integrins czl/?l, a2pl or a6@1 which belong to the RGD-insensitive cell receptors [6]. It also indicates that the high inhibiting activity of cRGDW peptide for vitronectin and laminin Pl adhesion is not due to cytotoxic or other effects unrelated to integrin recognition.…”

Section: Vitreneetin Baminin Plsupporting

confidence: 92%

“…Since we could only partially inhibit adhesion by either a P3-specific monoclonal antibody Cl7 [25] or an antiserum against fibronectin receptor with a strong titer for the pl subunit, the more recently described vitronectin receptors [6] av@l and possibly avB5 may also participale. Similar antibody inhibition patterns were also observed for adhesion to Iaminin Pl [21 J while an inhibiting monoclonal antibody to the fibronectin receptor &5 subunit was inactive.…”

Section: Resijlts and Discijssionmentioning

confidence: 84%

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Arg‐Gly‐Asp constrained within cyclic pentapoptides Strong and selective inhibitors of cell adhesion to vitronectin and laminin fragment P1

et al. 1991

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Cyclic Arg-Cly-Asp-Phe-Val peptides with either D-Pile or D-Val residues were 20-to more than IOO-fold better inhibitors of ccl1 adhesion to vitronectin and/or laminin fragment Pl when compared to a linear variant or Gly-Arg-Gly-Asp-Ser.No or only little increase in inhibitory capacity was observed for fibronectin adhesion and for the binding of platelet receptor aIIbj33 to fibrinogen. NMR studies of the two most active cyclic peptides showed for both an all-tram conformation with a PII' and y turn. Subtle conformational differences, however, exist between both peptides and may contribute to selectivity of inhibition.

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Section: Vitreneetin Baminin Plsupporting

confidence: 92%

Section: Resijlts and Discijssionmentioning

confidence: 84%

Arg‐Gly‐Asp constrained within cyclic pentapoptides Strong and selective inhibitors of cell adhesion to vitronectin and laminin fragment P1

et al. 1991

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“…This feature, which is known to be characteristic of the neoplastic phenotype (Ruoslahti, 1991), is consistent with the tumorigenic progression undergone by Caco-2-MT and Caco-2-T cells after functional insertion of Ha-ras or PyMT oncogenes Delage et al, 1993). Several arguments support the notion that p65 plays a critical role in the maintenance of cellular adhesion.…”

Section: Discussionsupporting

confidence: 72%

Down-regulation of NF-κB activity and NF-κB p65 subunit expression by ras and polyoma middle T oncogenes in human colonic Caco-2 cells

et al. 1997

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The products of ras and src proto-oncogenes are frequently activated in a constitutive state in human colorectal cancer. In this study we attempted to establish whether the tumorigenic progression induced by oncogenic activation of p21 ras or pp60 c-src in human colonic cells is associated with alterations of the activity and expression of nuclear factor kB (NF-kB), a transcription factor suspected to participate in the development of cancer. To this end, we used Caco-2 cells made highly tumorigenic by transfection with an activated Val-12 human Ha-ras gene or with the polyoma middle T (PyMT) oncogene, a constitutive activator of pp60 c-src tyrosine kinase activity. Compared with control vectortransfected Caco-2 cells, both oncogene-transfected cell lines exhibited: (i) decreased constitutive NF-kB DNAbinding activity and NF-kB-mediated reporter gene expression, without alteration of their response to TNF-a for activation of these parameters; (ii) reduced NF-kB cytosolic stores along with a decreased p65 expression due, at least in part, to destabilization of p65 mRNA; (iii) a decrease in adhesion to extracellular matrix component-coated substrata which was partially corrected when stimulating NF-kB transcriptional activity with TNF-a. These results indicate that the tumorigenic progression induced by oncogenic p21 ras or PyMT/pp60 c-src in human colonic Caco-2 cells is associated with a down-regulation of p65 expression and NF-kB activity which could be responsible for the reduced adhesive properties of these cells after oncogene transfection.

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“…As collagen-binding integrins have been shown to include a 1 b 1 , a 2 b 1 , and a 3 b 1 , depending on the cell type (Ruoslahti, 1991), and because these integrins are variously expressed by all of our cell lines, we conducted inhibition of adhesion and migration assays on type I collagen using function-blocking monoclonal antibodies directed against specific integrin subunits. Figure 5A and B demonstrate clearly that pancreatic cancer cell adhesion and migration on type I collagen is mediated exclusively by the a 2 b 1 integrin, and that neither the a 1 , a 3 , a 5 , or a 6 integrin subunits, nor the a v b 3 or a v b 5 integrins appear to be involved in the adhesive interactions between AsPC-1, BxPC-3, CFPAC, or FG pancreatic cancer cells and type I collagen.…”

Section: Type I Collagen Promotes Maximal Haptokinetic Cell Migrationmentioning

confidence: 99%

The α2β1 integrin mediates the malignant phenotype on type I collagen in pancreatic cancer cell lines

2006

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Pancreatic cancer is characterised by a hallmark desmoplastic response that includes upregulated expression of the extracellular matrix, and type I collagen in particular. Recent studies indicate that pancreatic cancer cells stimulate type I collagen synthesis in adjacent stellate cells, and that this upregulated type I collagen expression promotes the malignant phenotype in tumour cells as defined by increased proliferation, resistance to chemically induced apoptosis, and increased tumorigenesis. The integrin specificity of this interaction between type I collagen and tumour cells was not identified, however. In the present study, we examined eight pancreatic cancer cell lines for adhesion, proliferation, and migration, on types I and IV collagen, fibronectin, laminin, and vitronectin, as well as integrin expression. Our results indicate, for the overwhelming majority of cell lines, that type I collagen promotes the strongest adhesion, proliferation, and migration relative to the other substrates tested. Utilising function-blocking monoclonal antibodies directed against particular integrin subunits in cell adhesion and migration inhibition assays, we demonstrate further that the malignant phenotype on type I collagen is mediated specifically by the a 2 b 1 integrin. These results identify a 2 b 1 integrin-mediated adhesion to type I collagen as a potential therapeutic target in the treatment of pancreatic cancer.

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Integrins.

Cited by 1,495 publications

References 39 publications

Arg‐Gly‐Asp constrained within cyclic pentapoptides Strong and selective inhibitors of cell adhesion to vitronectin and laminin fragment P1

Arg‐Gly‐Asp constrained within cyclic pentapoptides Strong and selective inhibitors of cell adhesion to vitronectin and laminin fragment P1

Down-regulation of NF-κB activity and NF-κB p65 subunit expression by ras and polyoma middle T oncogenes in human colonic Caco-2 cells

The α2β1 integrin mediates the malignant phenotype on type I collagen in pancreatic cancer cell lines

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