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

Larry W. Kraiss, Andrew S. Weyrich, Neal M. Alto, Dan A. Dixon, Tina M. Ennis, Vijayanand Modur, Thomas M. McIntyre, Stephen M. Prescott, Guy A. Zimmerman

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)H1537-H1544
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume278
Issue number5 47-5
StatePublished - May 1 2000

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Keywords

  • Hemorheology
  • Phenotype
  • Phosphatidyl-inositol 3- kinase
  • Rapamycin
  • Signal transduction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Kraiss, L. W., Weyrich, A. S., Alto, N. M., Dixon, D. A., Ennis, T. M., Modur, V., McIntyre, T. M., Prescott, S. M., & Zimmerman, G. A. (2000). Fluid flow activates a regulator of translation, p70/p85 S6 kinase, in human endothelial cells. American Journal of Physiology - Heart and Circulatory Physiology, 278(5 47-5), H1537-H1544.