A novel protein interacts with the major transforming growth factor-beta responsive element in the plasminogen activator inhibitor type-1 gene.

Sandler, Manfred A.; Zhang, Jinan; Westerhausen, Donald; Billadello, Joseph J.

doi:10.1016/s0021-9258(17)31832-x

Cited by 29 publications

(1 citation statement)

References 41 publications

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“…This effect was attributed not to stimulation of endothelial proliferation but to growth of myofibroblasts, which presumably produce angiogenic factors. A major consequence of activation of TGF-13 by TSP1 is stimulation of PAI-1 production by many cells (26). PAI-1 could affect at least two steps that are important in angiogenesis: disruption of basement membranes and cell-matrix interactions.…”

Section: What Role Does Tsp1 Play In the Neoplastic Process And In Angiogenesis?mentioning

confidence: 99%

Diversity of function is inherent in matricellular proteins: an appraisal of thrombospondin 1.

Börnstein

1995

The Journal of Cell Biology

624

494

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R current appreciation of the involvement of hrombospondin 1 (TSP1) 1 in diverse biological processes (Fig. 1; 1, 3, 25) extends far beyond the role initially attributed to the protein in platelet aggregation and coagulation. This diversity of function has led to considerable confusion in the literature and skepticism among scientists that a single protein can subserve such protean, sometimes conflicting, functions. In this Commentary I will attempt to show that the ability of matricellular proteins, as defined below, to interact with a wide range of both matrix proteins and cell surface receptors can explain the complex biological functions of TSP1 and resolve many of the controversies regarding its mode of action. A conclusion of this analysis is that, even if allowances are made for some errors in experimentation and interpretation, the majority of the reported functions of TSP1, divergent as they appear to be, are likely to be correct.The term "matricellular" is used in this analysis to refer to a group of modular, extracellular proteins whose functions are achieved by binding to matrix proteins as well as to cell surface receptors, or to other molecules such as cytokines and proteases that interact, in turn, with the cell surface. In addition to TSP1, this group is likely to include members of the tenascin protein family, SPARC/osteonectin and its relatives, and osteopontin. Although matricellular proteins can be associated with structural elements such as collagen fibrils or basement membranes, it is presumed that they do not contribute to the structural integrity of these elements. An association could, nevertheless, serve to sequester matricellular proteins, and provide a source of the proteins for subsequent recruitment to the cell surface. It should be noted that the distinction between structural matrix and matricellular proteins is not complete, since proteins such as fibronectin and laminin, which do serve as integral components of structural elements, also have adhesive functions and play biological roles that partially overlap those of matricellular proteins. Furthermore, matricellular proteins may participate in the formation of structural complexes under some circum

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Section: What Role Does Tsp1 Play In the Neoplastic Process And In Angiogenesis?mentioning

confidence: 99%

Diversity of function is inherent in matricellular proteins: an appraisal of thrombospondin 1.

Börnstein

1995

The Journal of Cell Biology

624

494

View full text Add to dashboard Cite

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Transforming growth factor-β1 enhances the invasiveness of human MDA-MB-231 breast cancer cells by up-regulating urokinase activity

et al. 1998

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Transforming growth factor‐beta (TGFβ1) enhances human MDA‐MB‐231 breast tumour cell invasion of reconstituted basement membrane in vitro but does not inhibit proliferation of this cell line. In contrast to basal invasion, which is plasmin‐, urokinase (uPA)‐, tissue‐type plasminogen activator (t‐PA)‐, matrix metalloproteinase (MMP)‐9‐ and TIMP‐1‐inhibitable MMP‐dependent, TGFβ1 enhanced‐invasion is dependent upon plasmin and uPA activity but does not appear to involve t‐PA‐, MMP9‐ or TIMP‐1‐inhibitable MMPs, as judged by inhibitor studies. Enhanced invasion is associated with increased u‐PA, UPAR, PAI‐1, MT‐MMP‐1, MMP‐9 and TIMP‐1 expression; with reduced t‐PA, MMP‐1 and MMP‐3 expression; and with the induction of membrane MMP‐9 association. The net result of these changes includes increased secreted, but not membrane‐associated, uPA levels and activity and reduced secreted levels of plasmin and APMA‐activatable gelatinolytic, collagenolytic and caseinolytic MMP activity but no change in membrane‐associated gelatinolytic activity, despite increased MT‐MMP‐1 expression and MMP‐9 membrane association. TGFβ1 does not induce MMP‐2 expression. Our data indicate that TGFβ1 can promote the malignant behaviour of MDA‐MB‐231 cells refractory to TGFβ1‐mediated proliferation control by enhancing their invasive capacity. We suggest that this results from the action of a uPA/plasmin‐dependent mechanism resulting from stimulation of uPA expression, secretion and subsequent activity, despite elevated PAI‐1 inhibitor levels. Int. J. Cancer 75:721–730, 1998.© 1998 Wiley‐Liss, Inc.

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Transforming growth factor-beta induces senescence in hepatocellular carcinoma cells and inhibits tumor growth

Şentürk¹,

Mumcuoglu²,

et al. 2010

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Senescence induction could be used as an effective treatment for hepatocellular carcinoma (HCC). However, major senescence inducers (p53 and p16 Ink4a) are frequently inactivated in these cancers. We tested whether transforming growth factor-b (TGF-b) could serve as a potential senescence inducer in HCC. First, we screened for HCC cell lines with intact TGF-b signaling that leads to small mothers against decapentaplegic (Smad)-targeted gene activation. Five cell lines met this condition, and all of them displayed a strong senescence response to TGF-b1 (1-5 ng/mL) treatment. Upon treatment, c-myc was down-regulated, p21Cip1 and p15 Ink4bwere up-regulated, and cells were arrested at G 1 . The expression of p16 Ink4a was not induced, and the senescence response was independent of p53 status. A short exposure of less than 1 minute was sufficient for a robust senescence response. Forced expression of p21Cip1 and p15Ink4b recapitulated TGF-b1 effects. Senescence response was associated with reduced nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) induction and intracellular reactive oxygen species (ROS) accumulation. The treatment of cells with the ROS scavenger N-acetyl-L-cysteine, or silencing of the NOX4 gene, rescued p21 Cip1 and p15 Ink4b accumulation as well as the growth arrest in response to TGF-b. Human HCC tumors raised in immunodeficient mice also displayed TGF-b1-induced senescence. More importantly, peritumoral injection of TGFb1 (2 ng) at 4-day intervals reduced tumor growth by more than 75%. In contrast, the deletion of TGF-b receptor 2 abolished in vitro senescence response and greatly accelerated in vivo tumor growth. Conclusion: TGF-b induces p53-independent and p16 Ink4a -independent, but Nox4-dependent, p21 Cip1-dependent, p15 Ink4b-dependent, and ROS-dependent senescence arrest in well-differentiated HCC cells. Moreover, TGF-b-induced senescence in vivo is associated with a strong antitumor response against HCC. (HEPATOLOGY 2010;52:966-974)

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A novel protein interacts with the major transforming growth factor-beta responsive element in the plasminogen activator inhibitor type-1 gene.

Cited by 29 publications

References 41 publications

Diversity of function is inherent in matricellular proteins: an appraisal of thrombospondin 1.

Diversity of function is inherent in matricellular proteins: an appraisal of thrombospondin 1.

Transforming growth factor-β1 enhances the invasiveness of human MDA-MB-231 breast cancer cells by up-regulating urokinase activity

Transforming growth factor-beta induces senescence in hepatocellular carcinoma cells and inhibits tumor growth

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