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

Raj Kishore, Gangjian Qin, Corinne Luedemann, Evelyn Bord, Allison Hanley, Marcy Silver, Mary Gavin, David Goukassain, Douglas W. Losordo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

TNF-α modulates EC proliferation and thereby plays a central role in new blood vessel formation in physiologic and pathologic circumstances. TNF-α is known to downregulate cyclin A, a key cell cycle regulatory protein, but little else is known about how TNF-α 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-α-induced transcriptional represser. TNF-α 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-α-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-α regulates angiogenesis via Rho kinase induction of a transcriptional represser function of the cytoskeletal protein ezrin and that ezrin may represent a suitable therapeutic target for processes dependent on EC proliferation.

Original languageEnglish (US)
Pages (from-to)1785-1796
Number of pages12
JournalJournal of Clinical Investigation
Volume115
Issue number7
DOIs
StatePublished - Jul 2005

ASJC Scopus subject areas

  • Medicine(all)

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