Transcription of thrombomodulin mRNA in mouse hemangioma cells is increased by cycloheximide and thrombin.

Kumada, Toshihiko; Majerus, Philip W.

doi:10.1073/pnas.86.18.7179

Cited by 20 publications

(11 citation statements)

References 52 publications

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“…The implication of transcriptional regulation is supported by the fact that actinomycin D significantly prevented CHX-induced upregulation of RGS4 mRNA. It is also supported by previous studies in many other genes such as thrombomodulin (11), c-fos(21), ICAM-1 (56), and G-CSF receptor (66), etc. Another possibility is RGS4 mRNA stability and cotranslational regulation.…”

Section: Discussionsupporting

confidence: 80%

RNA-binding protein HuR regulates RGS4 mRNA stability in rabbit colonic smooth muscle cells

Liu

et al. 2010

American Journal of Physiology-Cell Physiology

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September 29, 2010; doi:10.1152/ajpcell.00093.2010.-Regulator of G protein signaling 4 (RGS4) regulates the strength and duration of G protein signaling and plays an important role in smooth muscle contraction, cardiac development, and psychiatric disorders. Little is known about the posttranscriptional regulation of RGS4 expression. We cloned the full-length cDNA of rabbit RGS4, which contains a long 3=-untranslated region (UTR) with several AU-rich elements (AREs). We determined whether RGS4 mRNA stability is mediated by the RNA-binding protein human antigen R (HuR) and contributes to IL-1␤-induced upregulation of RGS4 expression. We show that IL-1␤ treatment in colonic smooth muscle cells doubled the half-life of RGS4 mRNA. Addition of RGS4 3=-UTR to the downstream of Renilla luciferase reporter induced dramatic reduction in the enzyme activity and mRNA expression of luciferase, which was attenuated by the site-directed mutation of the two 3=-most ARE sites. IL-1␤ increased luciferase mRNA stability in a UTR-dependent manner. Knockdown of HuR significantly aggravated UTR-mediated instability of luciferase and inhibited IL-1␤-induced upregulation of RGS4 mRNA. In addition, IL-1␤ increased cytosolic translocation and RGS4 mRNA binding of HuR. These findings suggest that 3=-most ARE sites within RGS4 3=-UTR are essential for the instability of RGS4 mRNA and IL-1␤ promotes the stability of RGS4 mRNA through HuR.regulators of G protein signaling; Interleukin; AU-rich element REGULATOR OF G PROTEIN SIGNALING (RGS) proteins belong to a large family of highly diverse, multifunctional signaling proteins, which share a conserved signature domain (RGS domain) that binds directly to the activated G␣ subunits. RGS terminates G protein signaling by accelerating intrinsic GTPase activity of G␣ and thereby fostering reassociation of the G␣␤␥ trimer (61). Over 30 mammalian family members have been described so far and classified into seven subfamilies based on sequence identity and functional similarities (70,72). RGS4 is one of the most extensively studied RGS proteins (44,61,62,70,72) and regulates the strength and duration of the G␣ i/o and G␣ q/11 family members (26, 36). RGS4 plays an important role in promoting cardiac development, regulating neuronal plasticity, and modulating smooth muscle contraction (2). In cardiomyocytes, RGS4 expression is induced by endotoxin and interleukin (IL)-1␤ (57, 58) and contributes to the loss of G␣ q -mediated activation of phospholipase C (PLC) by endothelin-1 (51). In the central nervous system, RGS4 is linked to schizophrenia (6,14,27,44,46), Alzheimer disease (13), and Huntington disease (63). RGS4 regulates the pain process (17, 25) and morphine tolerance (25, 31) through modulation of opioid receptor signaling (43,69). In gastrointestinal smooth muscle, RGS4 negatively regulates G␣ q signaling activated by M3 or motilin receptors (37, 38) and thus inhibits agonistinduced initial contraction (33,35,36). Recently, we demonstrated (35) that treatment of colonic smooth muscle cells ...

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Section: Discussionsupporting

confidence: 80%

RNA-binding protein HuR regulates RGS4 mRNA stability in rabbit colonic smooth muscle cells

Liu

et al. 2010

American Journal of Physiology-Cell Physiology

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“…TM is transcriptionally upregulated by thrombin, vascular endothelial growth factor, histamine, dibutyryl cAMP, retinoic acid, theophylline, heat shock, and statins, [83][84][85][86][87][88][89] whereas shear stress, 90 hemodynamic forces, 91 hypoxia, oxidized low-density lipoprotein, and transforming growth factor-␤ 92,93 will suppress TM gene expression. 94 Although TNF␣ and IL-1␤ upregulate macrophage expression of TM, 95 these cytokines suppress TM in endothelial cells at transcriptional and posttranscriptional levels.…”

Section: Regulation Of Expression Of Tm and Epcrmentioning

confidence: 99%

Thrombomodulin-Protein C-EPCR System

Wouwer

Collen

Conway

2004

ATVB

316

151

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Abstract-Late in the 18th century, William Hewson recognized that the formation of a clot is characteristic of many febrile, inflammatory diseases (Owen C. A History of Blood Coagulation. Rochester, Minnesota: Mayo Foundation;. Since that time, there has been steady progress in our understanding of coagulation and inflammation, but it is only in the past few decades that the molecular mechanisms linking these 2 biologic systems have started to be delineated. Most of these can be traced to the vasculature, where the systems most intimately interact. Thrombomodulin (TM), a cell surface-expressed glycoprotein, predominantly synthesized by vascular endothelial cells, is a critical cofactor for thrombin-mediated activation of protein C (PC), an event further amplified by the endothelial cell protein C receptor (EPCR). Activated PC (APC), in turn, is best known for its natural anticoagulant properties. Recent evidence has revealed that TM, APC, and EPCR have activities that impact not only on coagulation but also on inflammation, fibrinolysis, and cell proliferation. This review highlights recent insights into the diverse functions of this complex multimolecular system and how its components are integrated to maintain homeostasis under hypercoagulable and/or proinflammatory stress conditions. Overall, the described advances underscore the usefulness of elucidating the relevant molecular pathways that link both systems for the development of novel therapeutic and diagnostic targets for a wide range of inflammatory diseases.

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“…Expression is affected by a range of pathophysiological stimuli (Maruyama et al, 1985;Dittman et al, 1989;Ohji et al, 1995;Calnek and Grinnell, 1998;Ishii et al, 2003;Shi et al, 2003) and the effect of a specific stimulus varies with the cell type involved (Grey et al, 1998).…”

mentioning

confidence: 99%

Thrombomodulin expression in colorectal carcinoma is protective and correlates with survival

et al. 2006

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Thrombomodulin (TM) is an endothelial receptor that exhibits anticoagulant, antifibrinolytic and anti-inflammatory activity by inhibiting thrombin and cellular adhesion. In this study, the expression and significance of TM was examined in primary colorectal cancer and its prognostic implications explored. TM immunostaining was performed on formalin-fixed, paraffin-embedded tissue sections, from primary lesions of 200 patients with colorectal carcinoma. Institutional Ethical approval was granted and clinical data retrieved from patients' records. All normal colonic tissue expressed TM on endothelial cells. TM tumour cell expression was demonstrated in 53 (26.5%) cases and 147 (73.5%) showed no neoplastic cell staining. On univariate and multivariate analysis TM expression on tumour cells correlated significantly with tumour stage, differentiation, Jass score and 5 year survival. TM expression decreases as overall stage and tumour size increase (P ¼ 0.03). In all, 91% TM positive tumours were well differentiated and 85% of TM negative tumours were poorly differentiated (Po0.01). Five year survival rates of patients with positive and negative TM expression were 71 and 41%, respectively. Survival rate was poorer in those patients who were TM negative compared with those who were positive (Po0.01). A total of 101 (50.5%) of the cases were node negative. In this group, 5 year survival rates of patients with positive and negative TM expression were 87.5 and 37.8%, respectively, demonstrating a poorer survival rate for those who are node negative and TM negative at the time of surgery (Po0.001). This study demonstrates that loss of TM is a key indicator in tumour biology and prognosis.

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Transcription of thrombomodulin mRNA in mouse hemangioma cells is increased by cycloheximide and thrombin.

Cited by 20 publications

References 52 publications

RNA-binding protein HuR regulates RGS4 mRNA stability in rabbit colonic smooth muscle cells

RNA-binding protein HuR regulates RGS4 mRNA stability in rabbit colonic smooth muscle cells

Thrombomodulin-Protein C-EPCR System

Thrombomodulin expression in colorectal carcinoma is protective and correlates with survival

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