Regulation of fibronectin matrix assembly by activated Ras in transformed cells

Brenner, Kerry A; Corbett, Siobhan; Schwarzbauer, Jean E.

doi:10.1038/sj.onc.1203626

Cited by 69 publications

(87 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This possibility is supported by data showing DPPIV binds to fibronectin and functions as an adhesion molecule (10), and that fibronectin on the cell surface disappears upon oncogenic transformation. Furthermore, overexpression of fibronectin leads to suppression of the transformed phenotype (49,50). Thus, loss of…”

Section: Discussionmentioning

confidence: 99%

Dipeptidyl Peptidase Inhibits Malignant Phenotype of Prostate Cancer Cells by Blocking Basic Fibroblast Growth Factor Signaling Pathway

2005

View full text Add to dashboard Cite

Dipeptidyl peptidase IV (DPPIV) is a serine protease with tumor suppressor function. It regulates the activities of mitogenic peptides implied in cancer development. Progression of benign prostate cancer to malignant metastasis is linked to increased production of basic fibroblast growth factor (bFGF), a powerful mitogen. In this study, using in vitro model system we show that DPPIV loss is associated with increased bFGF production in metastatic prostate cancer cells. DPPIV reexpression in prostate cancer cells blocks nuclear localization of bFGF, reduces bFGF levels, inhibits mitogenactivated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)1/2 activation, and decreases levels of urokinasetype plasminogen activator, known downstream effectors of bFGF signaling pathway. These molecular changes were accompanied by induction of apoptosis, cell cycle arrest, inhibition of in vitro cell migration, and invasion. Silencing of DPPIV by small interfering RNA resulted in increased bFGF levels and restoration of mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)1/2 activation. These results indicate that DPPIV inhibits the malignant phenotype of prostate cancer cells by blocking bFGF signaling pathway. (Cancer Res 2005; 65(4): 1325-34)

show abstract

Section: Discussionmentioning

confidence: 99%

Dipeptidyl Peptidase Inhibits Malignant Phenotype of Prostate Cancer Cells by Blocking Basic Fibroblast Growth Factor Signaling Pathway

2005

View full text Add to dashboard Cite

show abstract

“…In EpH4 cells, TN-C is expressed as a single 7.5 kb mRNA, corresponding to a splice variant also found in HC11 cells (Wirl et al, 1995 (Carnemolla et al, 1992;Brenner et al, 2000).…”

Section: Oncogenic Ras Induces Tn-c Transcription While Ras Plus Tgfbmentioning

confidence: 99%

Enhanced tenascin-C expression and matrix deposition during Ras/TGF-β-induced progression of mammary tumor cells

et al. 2004

View full text Add to dashboard Cite

Overexpression of tenascin-C (TN-C) in breast carcinomas has been associated with a migratory or even invasive tumor cell phenotype. The mechanisms regulating expression and matrix deposition of TN-C in normal and cancerous breast tissues are, however, little understood. Here, we demonstrate that mouse mammary epithelial cells (EpH4) transformed by oncogenic Ha-Ras (EpRas) overexpress TN-C, which accumulates in the cytoplasm. When EpRas cells undergo epithelial-mesenchymal transition (EMT) in response to TGFb1, they secrete TN-C into the culture medium. In EpRas cells undergoing TGFb1-induced EMT in three-dimensional (3D)-collagen gel cultures, TN-C was deposited into an extracellular matrix (ECM) already containing fibronectin and perlecan. Under less physiological 2D plastic cultures, EpRas cells undergoing EMT failed to deposit TN-C into an (apparently incomplete) ECM. Ras-downstream signaling was dissected by pharmacological inhibitors and effectorspecific Ras mutants (V12S35, V12C40), specifically inhibiting or activating ERK/MAPK or PI3K signaling, respectively. We showed that TN-C overexpression required a hyperactive ERK/MAPK-signaling pathway, while elevated PI3K signaling did not enhance TN-C expression. Similarly, tumors induced by cells exhibiting hyperactive ERK/MAPK signaling showed expression of TN-C in the tumor cells themselves, while only endothelial cells expressed TN-C in tumors caused by the V12C40 mutant (incapable of EMT in vivo). Taken together, our data indicate that hyperactive ERK/MAPK signaling causes enhanced expression of TN-C, while its secretion is induced by TGFb1 and both signals cooperate in TN-C matrix deposition. Importantly, both signals also cooperate to induce EMT in vitro and tumor progression/ metastasis in vivo.

show abstract

“…Cells were then incubated with 25 g/ml human pFN for 2 h, after which time cells were washed with PBS ϩ 0.5 mM MgCl 2 and then fixed with 3.7% formaldehyde in PBS for 15 min at room temperature. FN matrix was detected with culture supernatant from hybridoma cells producing anti-human FN antibody 7.1 at 1:200 (Brenner et al, 2000) and fluorescein-conjugated goat antimouse secondary antibody (Molecular Probes Inc.) at 1:500. Coverslips were mounted with SlowFade Light Antifade Kit (Molecular Probes Inc.).…”

Section: Immunofluorescencementioning

confidence: 99%

Tenascin-C Modulates Matrix Contraction via Focal Adhesion Kinase– and Rho-mediated Signaling Pathways

Midwood

Schwarzbauer

2002

MBoC

130

View full text Add to dashboard Cite

A provisional matrix consisting of fibrin and fibronectin (FN) is deposited at sites of tissue damage and repair. This matrix serves as a scaffold for fibroblast migration into the wound where these cells deposit new matrix to replace lost or damaged tissue and eventually contract the matrix to bring the margins of the wound together. Tenascin-C is expressed transiently during wound repair in tissue adjacent to areas of injury and contacts the provisional matrix in vivo. Using a synthetic model of the provisional matrix, we have found that tenascin-C regulates cell responses to a fibrin-FN matrix through modulation of focal adhesion kinase (FAK) and RhoA activation. Cells on fibrin-FN+tenascin-C redistribute their actin to the cell cortex, downregulate focal adhesion formation, and do not assemble a FN matrix. Cells surrounded by a fibrin-FN+tenascin-C matrix are unable to induce matrix contraction. The inhibitory effect of tenascin-C is circumvented by downstream activation of RhoA. FAK is also required for matrix contraction and the absence of FAK cannot be overcome by activation of RhoA. These observations show dual requirements for both FAK and RhoA activities during contraction of a fibrin-FN matrix. The effects of tenascin-C combined with its location around the wound bed suggest that this protein regulates fundamental processes of tissue repair by limiting the extent of matrix deposition and contraction to fibrin-FN-rich matrix in the primary wound area.

show abstract

Regulation of fibronectin matrix assembly by activated Ras in transformed cells

Cited by 69 publications

References 64 publications

Dipeptidyl Peptidase Inhibits Malignant Phenotype of Prostate Cancer Cells by Blocking Basic Fibroblast Growth Factor Signaling Pathway

Dipeptidyl Peptidase Inhibits Malignant Phenotype of Prostate Cancer Cells by Blocking Basic Fibroblast Growth Factor Signaling Pathway

Enhanced tenascin-C expression and matrix deposition during Ras/TGF-β-induced progression of mammary tumor cells

Tenascin-C Modulates Matrix Contraction via Focal Adhesion Kinase– and Rho-mediated Signaling Pathways

Contact Info

Product

Resources

About