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Neddylation pathway regulates the proliferation and survival of macrophages

Title
Neddylation pathway regulates the proliferation and survival of macrophages
Authors
Li L.Liu B.Dong T.Lee H.W.Yu J.Zheng Y.Gao H.Zhang Y.Chu Y.Liu G.Niu W.Zheng S.Jeong L.S.Jia L.
Ewha Authors
정낙신
Issue Date
2013
Journal Title
Biochemical and Biophysical Research Communications
ISSN
0006-291XJCR Link
Citation
vol. 432, no. 3, pp. 494 - 498
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Neddylation is a new type of protein post-translational modification which adds the ubiquitin-like molecule Nedd8 to target proteins. The well-identified targets of neddylation are cullins, which serve as essential components of Cullin-RING E3 ligases (CRL). It is reported that inhibition of neddylation repressed NF-κB-mediated proinflammatory cytokine production in macrophages. However, the role of neddylation in the proliferation and survival of macrophages has not been well defined. Here we report that partial inactivation of the neddylation pathway by a specific Nedd8-activating enzyme E1 (NAE) inhibitor MLN4924 reduced LPS-induced production of the proinflammatory cytokines TNF-α and IL-6 without obvious impairment of cell viability. However, persistent and severe inactivation of neddylation by MLN4924 significantly inhibited cell proliferation by inducing G2 phase cell-cycle arrest and further triggered cell death by inducing apoptosis in RAW264.7 macrophages. Mechanistic analysis revealed that inactivation of neddylation blocked cullin neddylation, inhibited CRL E3 ligase activity, and thus led to the accumulation of CRL substrates, resulting in cell-cycle arrest, DNA damage response and apoptosis. The findings revealed that neddylation serves as an important signaling pathway regulating the proliferation and survival of macrophages. © 2013 Elsevier Inc.
DOI
10.1016/j.bbrc.2013.02.028
Appears in Collections:
약학대학 > 약학과 > Journal papers
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