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Big mitogen-activated protein kinase 1/extracellular signal-regulated kinase 5 signaling pathway is essential for tumor-associated angiogenesis

Academic Article
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Overview

authors

  • Hayashi, M.
  • Fearns, C.
  • Eliceiri, B.
  • Yang, Y.
  • Lee, Jiing-Dwan

publication date

  • September 2005

journal

  • Cancer Research  Journal

abstract

  • Although big mitogen-activated protein kinase 1 (BMK1) has been shown to be critical for embryonic angiogenesis, the role of BMK1 in tumor-associated neovascularization is poorly understood. Exogenous tumors were established in BMK1+/+, BMK1flox/+, or BMK1flox/flox mice carrying the Mx1-Cre transgene. Induced deletion of host BMK1 gene significantly reduced the volumes of B16F10 and LL/2 tumor xenografts in BMK1flox/flox mice by 63% and 72%, respectively. Examining the tumors in these induced BMK1-knockout animals showed a significant decrease in vascular density. Localized reexpression of BMK1 in BMK1-knockout mice by administration of adenovirus encoding BMK1 restored tumor growth and angiogenesis to the levels observed in wild-type mice. These observations were further supported by in vivo Matrigel plug assays in which vascular endothelial growth factor- and basic fibroblast growth factor-induced neovacularization was impaired by removing BMK1. Through screening with the Pepchip microarray, we discovered that in BMK1-knockout endothelial cells, phosphorylation of ribosomal protein S6 (rpS6) at Ser235/236 was mostly abrogated, and this BMK1-dependent phosphorylation required the activity of p90 ribosomal S6 kinase (RSK). Immunofluorescent analysis of tumor vasculature from BMK1-knockout and control animals revealed a strong correlation between the presence of BMK1 and the phosphorylation of rpS6 in tumor-associated endothelial cells of blood vessels. As both RSK and rpS6 are known to be important for cell proliferation and survival, which are critical endothelial cell functions during neovascularization, these findings suggest that the BMK1 pathway is crucial for tumor-associated angiogenesis through its role in the regulation of the RSK-rpS6 signaling module.

subject areas

  • Amino Acid Sequence
  • Animals
  • Carcinoma, Lewis Lung
  • Cell Movement
  • Endothelial Cells
  • Fibroblast Growth Factor 2
  • Humans
  • MAP Kinase Signaling System
  • Melanoma, Experimental
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 7
  • Molecular Sequence Data
  • Neovascularization, Pathologic
  • Phosphorylation
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Ribosomal Proteins
  • Transplantation, Heterologous
  • Vascular Endothelial Growth Factor A
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Identity

International Standard Serial Number (ISSN)

  • 0008-5472

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.can-04-4540

PubMed ID

  • 16140937
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Additional Document Info

start page

  • 7699

end page

  • 7706

volume

  • 65

issue

  • 17

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