0000000000625183
AUTHOR
Bernd Schmeck
Rho protein inactivation induced apoptosis of cultured human endothelial cells.
Small GTP-binding Rho GTPases regulate important signaling pathways in endothelial cells, but little is known about their role in endothelial cell apoptosis. Clostridial cytotoxins specifically inactivate GTPases by glucosylation [ Clostridium difficile toxin B-10463 (TcdB-10463), C. difficile toxin B-1470 (TcdB-1470)] or ADP ribosylation ( C. botulinum C3 toxin). Exposure of human umbilical cord vein endothelial cells (HUVEC) to TcdB-10463, which inhibits RhoA/Rac1/Cdc42, or to C3 toxin, which inhibits RhoA, -B, -C, resulted in apoptosis, whereas inactivation of Rac1/Cdc42 with TcdB-1470 was without effect, suggesting that Rho inhibition was responsible for endothelial apoptosis. Disruptio…
Reduction of tumor necrosis factor-alpha (TNF-α) related nuclear factor-kappaB (NF-κB) translocation but not inhibitor kappa-B (Iκ-B)-degradation by Rho protein inhibition in human endothelial cells
Degradation of inhibitor kappa-B (Ikappa-B) followed by translocation of nuclear factor-kappaB (NF-kappaB) into the nucleus and activation of gene expression is essential in tumor necrosis factor-alpha (TNF-alpha)-signaling. In order to analyze the role of Rho proteins in TNF-alpha-induced NF-kappaB-activation in human umbilical cord vein endothelial cells (HUVEC) we used Clostridium difficile toxin B-10463 (TcdB-10463) which inactivates RhoA/Rac1/Cdc42 by glucosylation and Clostridium botulinum C3-toxin which inhibits RhoA/B/C by ADP-ribosylation. Exposure of HUVEC to 10 ng/mL TcdB-10463 or 2.5 microg/mL C3-toxin inhibited TNF-alpha (100 ng/mL)-induced expression of a NF-kappaB-dependent r…
Pro- and Antitumorigenic Capacity of Immunoproteasomes in Shaping the Tumor Microenvironment
Abstract Apart from the constitutive proteasome, the immunoproteasome that comprises the three proteolytic subunits LMP2, MECL-1, and LMP7 is expressed in most immune cells. In this study, we describe opposing roles for immunoproteasomes in regulating the tumor microenvironment (TME). During chronic inflammation, immunoproteasomes modulated the expression of protumorigenic cytokines and chemokines and enhanced infiltration of innate immune cells, thus triggering the onset of colitis-associated carcinogenesis (CAC) in wild-type mice. Consequently, immunoproteasome-deficient animals (LMP2/MECL-1/LMP7–null mice) were almost completely resistant to CAC development. In patients with ulcerative c…