Fluid flow activates a regulator of translation, p70/p85 S6 kinase, in human endothelial cells

1  Division of Vascular Surgery, Department of Surgery; 2  Program in Human Molecular Biology and Genetics, Eccles Institute of Human Genetics; 3  Surgical Service, Salt Lake Veterans Affairs Medical Center; and Departments of 4  Internal Medicine, 5  Pathology, and 6  Biochemistry, University of Ut...

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Published in:American journal of physiology. Heart and circulatory physiology 2000-05, Vol.278 (5), p.H1537-H1544
Main Authors: Kraiss, Larry W, Weyrich, Andrew S, Alto, Neal M, Dixon, Dan A, Ennis, Tina M, Modur, Vijayanand, McIntyre, Thomas M, Prescott, Stephen M, Zimmerman, Guy A
Format: Article
Language:English
Subjects:
3T3 Cells
Androstadienes - pharmacology
Animals
Blood Flow Velocity - physiology
Blotting, Western
Cells, Cultured
Endothelium, Vascular - cytology
Endothelium, Vascular - drug effects
Endothelium, Vascular - enzymology
Enzyme Activation - drug effects
Enzyme Activation - genetics
Humans
Immunosuppressive Agents - pharmacology
Mice
Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Phosphorylation
Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors
Protein Isoforms - metabolism
Protein Kinases
Proto-Oncogene Proteins - antagonists & inhibitors
Proto-Oncogene Proteins - biosynthesis
Ribosomal Protein S6 Kinases - genetics
Ribosomal Protein S6 Kinases - metabolism
RNA, Messenger - biosynthesis
Sirolimus - pharmacology
Space life sciences
Stress, Mechanical
Tacrolimus - pharmacology
TOR Serine-Threonine Kinases
Transcription Factors - metabolism
Transcription, Genetic - physiology
Viscosity
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Summary:1  Division of Vascular Surgery, Department of Surgery; 2  Program in Human Molecular Biology and Genetics, Eccles Institute of Human Genetics; 3  Surgical Service, Salt Lake Veterans Affairs Medical Center; and Departments of 4  Internal Medicine, 5  Pathology, and 6  Biochemistry, University of Utah, Salt Lake City, Utah 84112 Cellular phenotype is determined not only by genetic transcription but also by subsequent translation of mRNA into protein. Extracellular signals trigger intracellular pathways that distinctly activate translation. The 70/85-kDa S6 kinase (pp70 S6k ) is a central enzyme in the signal-dependent control of translation, but its regulation in endothelial cells is largely unknown. Here we show that fluid flow (in the absence of an exogenous mitogen) as well as humoral agonists activate endothelial pp70 S6k . Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), and wortmannin, a phosphatidylinositol 3-kinase inhibitor, blocked flow-induced pp70 S6k activation; FK-506, a rapamycin analog with minimal mTOR inhibitory activity, and PD-98059, an inhibitor of the flow-sensitive mitogen-activated protein kinase pathway, had no effect. Synthesis of Bcl-3, a protein whose translation is controlled by an mTOR-dependent pathway, was induced by flow and inhibited by rapamycin and wortmannin. Transcriptional blockade did not abolish the flow-induced upregulation of Bcl-3. Fluid forces may therefore modify endothelial phenotype by specifically regulating translation of certain mRNA transcripts into protein. signal transduction; hemorheology; rapamycin; phosphatidylinositol 3-kinase; phenotype
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.2000.278.5.h1537