The cytoskeletal protein ezrin regulates EC proliferation and angiogenesis via TNF-alpha-induced transcriptional repression of cyclin A.
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.
Kishore
Raj
R
Division of Cardiovascular Research, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA. raj.kishore@tufts.edu
Qin
Gangjian
G
Luedemann
Corinne
C
Bord
Evelyn
E
Hanley
Allison
A
Silver
Marcy
M
Gavin
Mary
M
Yoon
Young-sup
YS
Goukassian
David
D
Goukassain
David
D
Losordo
Douglas W
DW
D000818:Animals; D002417:Cattle; D049109:Cell Proliferation; D019925:Cyclin A / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology* / Q000502:physiology / Q000637:transplantation; D005121:Extremities; D015870:Gene Expression; D006801:Humans; D007511:Ischemia / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D018919:Neovascularization, Physiologic; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000099149:Ezrin
D019925:Cyclin A; D003598:Cytoskeletal Proteins; D010750:Phosphoproteins; D014409:Tumor Necrosis Factor-alpha; D000099149:Ezrin