期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 115, 期 7, 页码 1785-1796出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI22849
关键词
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资金
- NHLBI NIH HHS [R01 HL63414, R01 HL063414, P01 HL066957, HL63695, R37 HL053354, HL66957, R01 HL053354, HL53354, R01 HL057516, R01 HL063695, HL57516] Funding Source: Medline
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-a. 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-a. 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-a-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.
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