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

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

Author information

1
Division of Cardiovascular Research, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA. raj.kishore@tufts.edu

Erratum in

  • J Clin Invest. 2005 Oct;115(10):2955. Yoon, Young-sup [added].
  • J Clin Invest. 2005 Aug;115(8):2297. Goukassain, David [corrected to Goukassian, David].

Abstract

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.

PMID:
15965500
PMCID:
PMC1150283
DOI:
10.1172/JCI22849
[Indexed for MEDLINE]
Free PMC Article

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