Phorbol Ester Activation of a Proteolytic Cascade Capable of Activating Latent Transforming Growth Factor-β

Guo, Meng; Mathieu, Patricia; Linebaugh, Bruce E.; Sloane, Bonnie F.; Reiners, John J.

doi:10.1074/jbc.m108180200

Cited by 86 publications

(51 citation statements)

References 75 publications

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“…Similarly, invasion of melanoma cells is prompted by stromal fibroblasts in a way that is associated with both TGF-␤1 activation and Cats B and L activities (61). Also, TGF-␤1 might be activated through a process initiated by Cat B (62). On the other hand, silencing of Cat B, but not Cat L, had a significant effect on ␣-SMA protein and mRNA levels during differentiation of CCD-19Lu cells.…”

Section: Discussionmentioning

confidence: 90%

Regulation of TGF-β1-driven Differentiation of Human Lung Fibroblasts

Kasabova

Joulin-Giet

Lecaille

et al. 2014

Journal of Biological Chemistry

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Background: Proteolytic events are involved in the progression of lung fibrosis. Results: Cathepsin B participates in lung fibroblast differentiation by triggering TGF-␤1/Smad pathway. TGF-␤1 up-regulates secretion of cystatin C. Conclusion: TGF-␤1 promotes cystatin C-dependent inhibition of extracellular matrix-degrading cathepsins. Significance: Both cathepsin B and cystatin C could play a crucial role in fibrosis by favoring accumulation of ECM.

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Section: Discussionmentioning

confidence: 90%

Regulation of TGF-β1-driven Differentiation of Human Lung Fibroblasts

Kasabova

Joulin-Giet

Lecaille

et al. 2014

Journal of Biological Chemistry

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“…Although we have proposed a role for cysteine protease Cat S in angiogenesis and presumably in tumor growth, we have had no direct in vivo evidence for or any mechanistic explanation of Cat S involvement. Several in vitro experiments demonstrated cysteine protease activities in the generation of anti-angiogenic endostatin (32,33), conversion of pro-angiogenic factor TGF-␤ (51,52), and activation of tumor invasionassociated urokinase-type plasminogen activator (53). It remains uncertain whether these in vitro activities of cysteine proteases have any pathophysiologic relevance in vivo.…”

Section: Discussionmentioning

confidence: 99%

Cathepsin S Controls Angiogenesis and Tumor Growth via Matrix-derived Angiogenic Factors

Wang

Sun

Kitamoto

et al. 2006

Journal of Biological Chemistry

251

196

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The cysteine protease cathepsin S is highly expressed in malignant tissues. By using a mouse model of multistage murine pancreatic islet cell carcinogenesis in which cysteine cathepsin activity has been functionally implicated, we demonstrated that selective cathepsin S deficiency impaired angiogenesis and tumor cell proliferation, thereby impairing angiogenic islet formation and the growth of solid tumors, whereas the absence of its endogenous inhibitor cystatin C resulted in opposite phenotypes. Although mitogenic vascular endothelial growth factor, transforming growth factor-␤1, and the anti-angiogenic endostatin levels in either serum or carcinoma tissue extracts did not change in cathepsin S-or cystatin C-null mice, tumor tissue basic fibroblast growth factor and serum type 1 insulin growth factor levels were higher in cystatin C-null mice, and serum type 1 insulin growth factor levels were also increased in cathepsin S-null mice. Furthermore, cathepsin S affected the production of type IV collagen-derived anti-angiogenic peptides and the generation of bioactive pro-angiogenic ␥2 fragments from laminin-5, revealing a functional role for cathepsin S in angiogenesis and neoplastic progression.Angiogenesis, the development of the microvasculature, is an essential process occurring under many pathological and physiological circumstances and depends on tightly controlled interactions between cells and extracellular matrix (ECM) 2 mediated by integral membrane proteins. These include integrins, which provide a link between ECM and the cytoskeleton, and extracellular proteases and their inhibitors, which mediate focal degradation of ECM components (1, 2), generate cell growth factors (3), and produce angiogenic regulatory factors (4).Lysosomal cysteine protease cathepsins have been shown to be highly expressed in human and murine tumors (5), where angiogenesis plays essential roles. Interruption of their expression either by antisense RNA (6) or RNA interference (7, 8) reduced tumor cell invasion, angiogenesis, and tumor growth. A recent study also demonstrated that inhibition of the activities of cysteine proteases with a broad inhibitor reduced angiogenesis and growth of pancreatic ␤-cell islet carcinoma in mice with an SV40 T antigen (Tag) transgene driven by the rat insulin II promoter (RIP1-Tag2) (9). Administration of JPM-ethyl ester (10), which affects all activities of cysteinyl cathepsins, significantly diminished the angiogenic switch, tumor burden, and tumor cell proliferation (11). However, many important questions are still unanswered; for example, which cathepsin(s) is the most important and by what mechanisms do these cysteinyl cathepsins affect tumor progression? Earlier studies suggested the importance of cathepsin (Cat) B in tumor angiogenesis and growth (6 -8). However, additional studies also demonstrated constitutive expression of Cat B in several cell types or tissues (12, 13). Therefore, cathepsins other than Cat B may also be involved in angiogenesis, tumor growth, cell proliferation, and...

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“…10,15 The activation of TGF-b by the matricellular protein trombospondin-1, 16 as well as by the integrin a v b 6 17,18 seem to proceed via similar mechanisms. In addition, a number of proteases including plasmin, 19,20 matrix metalloproteinases MMP-3, -9, and MT1-MMP, 21,22 as well as exocytosed cathepsin B 23 have been identified as activators of latent TGF-b, at least in vitro.…”

Section: Introductionmentioning

confidence: 99%

Apoptosis of human endothelial cells is accompanied by proteolytic processing of latent TGF-β binding proteins and activation of TGF-β

Solovyan

Keski‐Oja

2005

Cell Death Differ

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Transforming growth factors b (TGF-bs) are multifunctional cytokines that modulate cell growth, differentiation and apoptosis. Numerous effects initiated by TGF-bs in vitro have been described, but the role of TGF-b targeting and activation under physiological conditions has gained very little attention and understanding. We report here that apoptosis of human umbilical vein endothelial cells (HUVECs) is accompanied by release of truncated large latent TGF-b complexes from the pericellular matrix followed by activation of TGF-b. The activation of TGF-b during apoptosis was accompanied by enhanced secretion of b1-LAP protein, and apoptotic HUVECs acquired the capacity to induce the release of latent TGF-bbinding proteins (LTBPs) from extracellular matrices. Activated TGF-b, in turn, attenuated apoptotic death of HUVECs. Current results indicate that the activation of TGF-b accompanies the apoptosis of HUVECs, and may play a protective feedback role against apoptotic cell death. The results suggest a role for TGF-b as a putative extracellular modulator of apoptosis.

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Phorbol Ester Activation of a Proteolytic Cascade Capable of Activating Latent Transforming Growth Factor-β

Abstract: 12-O-

Cited by 86 publications

References 75 publications

Regulation of TGF-β1-driven Differentiation of Human Lung Fibroblasts

Regulation of TGF-β1-driven Differentiation of Human Lung Fibroblasts

Cathepsin S Controls Angiogenesis and Tumor Growth via Matrix-derived Angiogenic Factors

Apoptosis of human endothelial cells is accompanied by proteolytic processing of latent TGF-β binding proteins and activation of TGF-β

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