The cytoskeletal protein ezrin regulates EC proliferation and angiogenesis via TNF-alpha-induced transcriptional repression of cyclin A

J Clin Invest. 2005 Jul;115(7):1785-96. doi: 10.1172/JCI22849. Epub 2005 Jun 16.


TNF-alpha modulates EC proliferation and thereby plays a central role in new blood vessel formation in physiologic and pathologic circumstances. TNF-alpha is known to downregulate cyclin A, a key cell cycle regulatory protein, but little else is known about how TNF-alpha modulates EC cell cycle and angiogenesis. Using primary ECs, we show that ezrin, previously considered to act primarily as a cytoskeletal protein and in cytoplasmic signaling, is a TNF-alpha-induced transcriptional repressor. TNF-alpha exposure leads to Rho kinase-mediated phosphorylation of ezrin, which translocates to the nucleus and binds to cell cycle homology region repressor elements within the cyclin A promoter. Overexpression of dominant-negative ezrin blocks TNF-alpha-induced modulation of ezrin function and rescues cyclin A expression and EC proliferation. In vivo, blockade of ezrin leads to enhanced transplanted EC proliferation and angiogenesis in a mouse hind limb ischemia model. These observations suggest that TNF-alpha regulates angiogenesis via Rho kinase induction of a transcriptional repressor function of the cytoskeletal protein ezrin and that ezrin may represent a suitable therapeutic target for processes dependent on EC proliferation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cattle
  • Cell Proliferation
  • Cyclin A / genetics*
  • Cytoskeletal Proteins / deficiency
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / physiology*
  • Endothelial Cells / cytology*
  • Endothelial Cells / physiology
  • Endothelial Cells / transplantation
  • Extremities
  • Gene Expression
  • Humans
  • Ischemia / therapy
  • Mice
  • Mice, Nude
  • Neovascularization, Physiologic
  • Phosphoproteins / deficiency
  • Phosphoproteins / genetics
  • Phosphoproteins / physiology*
  • Transcription, Genetic
  • Transfection
  • Tumor Necrosis Factor-alpha / metabolism*


  • Cyclin A
  • Cytoskeletal Proteins
  • Phosphoproteins
  • Tumor Necrosis Factor-alpha
  • ezrin