Ubiquitin carboxyl terminal hydrolase L1 negatively regulates TNFalpha-mediated vascular smooth muscle cell proliferation via suppressing ERK activation.
Deubiquitinating enzymes (DUBs) appear to be critical regulators of a multitude of processes such as proliferation, apoptosis, differentiation, and inflammation. We have recently demonstrated that a DUB of ubiquitin carboxyl terminal hydrolase L1 (UCH-L1) inhibits vascular lesion formation via suppressing inflammatory responses in vasculature. However, the precise underlying mechanism remains to be defined. Herein, we report that a posttranscriptional up-regulation of UCH-L1 provides a negative feedback to tumor necrosis factor alpha (TNFalpha)-mediated activation of extracellular signal-regulated kinases (ERK) and proliferation in vascular smooth muscle cells (VSMCs). In rat adult VSMCs, adenoviral over-expression of UCH-L1 inhibited TNFalpha-induced activation of ERK and DNA synthesis. In contrast, over-expression of UCH-L1 did not affect platelet derived growth factor (PDGF)-induced VSMC proliferation and activation of growth stimulating cascades including ERK. TNFalpha hardly altered UCH-L1 mRNA expression and stability; however, up-regulated UCH-L1 protein expression via increasing UCH-L1 translation. These results uncover a novel mechanism by which UCH-L1 suppresses vascular inflammation.
Ichikawa
Tomonaga
T
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
Li
Jinqing
J
Dong
Xiaoyu
X
Potts
Jay D
JD
Tang
Dong-Qi
DQ
Li
Dong-Sheng
DS
Cui
Taixing
T
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D014176:Protein Biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D014657:Vasculitis / Q000201:enzymology
D014409:Tumor Necrosis Factor-alpha; C482860:UCHL1 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D043222:Ubiquitin Thiolesterase