title: MTUS1 silencing promotes E-selectin production through p38 MAPK-dependent CREB ubiquitination in endothelial cells.
abstract: BACKGROUND
  Endothelial cell activation is thought to be a key event in atherosclerosis. p38 mitogen-activated protein kinase (p38 MAPK) plays an important role in regulating pro-inflammatory cytokine production in endothelial cells (ECs), however, how p38 MAPK is controlled in EC activation remain unclear. In this study, we investigated the effect of mitochondrial tumor suppressor 1 (MTUS1) on p38 MAPK activation, cytokine induction and the underlying molecular mechanisms in ECs.
  
  
  RESULTS
  Using qPCR and ELISA methods, we found that knockdown of MTUS1 led to a marked increase in the mRNA and protein expression of E-selectin (SELE) and monocyte chemotactic protein-1 in ECs, which is accompanied with increased phosphorylation of p38 MAPK (Thr180/Tyr182), MKK3/6 (Ser 189) and IκBα (Ser 32). Using luciferase reporter assay, we found that MTUS1 silencing also activated NF-κB transcriptional activity. The inhibition of p38 MAPK and NF-κB pathway was shown to abrogate MTUS1 silencing-induced cytokine expression in ECs. Furthermore, MTUS1 silencing induced p38 MAPK-dependent ubiquitination of cAMP-response element binding protein (CREB) which potentiated CREB-binding protein-mediated NF-κB p65 acetylation and binding to the promoter of the SELE gene. Conversely, adenovirus-mediated overexpression of MTUS1 inhibited p38 MAPK activation in ECs in vitro and in vivo. Importantly, decreased expression of MTUS1 and CREB, accompanied with induced activation of p38 MAPK were observed in aortas of apoE-/- mice after high-fat diet challenge.
  
  
  CONCLUSIONS
  Our findings showed that MTUS1 regulates the p38 MAPK-mediated cytokine production in ECs. MTUS1 gene probably plays a protective role against pro-inflammatory response of ECs.
authors: Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors: Yinfang
authors: Y
authors: Wang
authors: Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors: Xiuqin
authors: X
authors: Dai
authors: Department of Cardiovascular Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors: Youbin
authors: Y
authors: Liu
authors: Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors: Jinping
authors: J
authors: Li
authors: Department of Cardiovascular Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors: Zongjun
authors: Z
authors: Liu
authors: Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors: Peihao
authors: P
authors: Yin
authors: Sino-German Laboratory for Molecular Medicine, Key Laboratory for Clinical Cardiovascular Genetics, Ministry of Education, Fuwai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors: Jingzhou
authors: J
authors: Chen
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic, Florida 32224, USA.
authors: Ying
authors: Y
authors: Wang
authors: The Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China.
authors: Nanping
authors: N
authors: Wang
authors: Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: zhangnep@hotmail.com.
authors: Peng
authors: P
authors: Zhang
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019040:E-Selectin / Q000096:biosynthesis*; D042783:Endothelial Cells / Q000378:metabolism*; D015870:Gene Expression; D020868:Gene Silencing; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D054875:Ubiquitination; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D019040:E-Selectin; C474762:MTUS1 protein, human; D016328:NF-kappa B; C546936:SELE protein, human; D025521:Tumor Suppressor Proteins; D048051:p38 Mitogen-Activated Protein Kinases
keywords: CREB; E-selectin; Endothelial cells; MTUS1; p38 MAPK