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A Cytoplasmic NF-kB Interacting Long Noncoding RNA Blocks IkB Phosphorylation and Suppresses Breast Cancer Metastasis

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摘要 : NF-kB is a critical link between inflammation and cancer, but whether long non-coding RNAs (lncRNAs) regulate its activation remains unknown. Here, we identify an NF-KappaB Interacting LncRNA (NKILA), which is upregulated by NF-kB, binds to NF-kB/IkB, and directly masks phosphorylation motifs of IkB, thereby inhibiting IKK-induced IkB phosphorylation and NF-kB activation. Unlike DNA that is dissociated from NF-kB by IkB, NKILA interacts with NF-kB/IkB to form a stable complex. Importantly, NKILA
NF-kB is a critical link between inflammation and cancer, but whether long non-coding RNAs (lncRNAs) regulate its activation remains unknown. Here, we identify an NF-KappaB Interacting LncRNA (NKILA), which is upregulated by NF-kB, binds to NF-kB/IkB, and directly masks phosphorylation motifs of IkB, thereby inhibiting IKK-induced IkB phosphorylation and NF-kB activation. Unlike DNA that is dissociated from NF-kB by IkB, NKILA interacts with NF-kB/IkB to form a stable complex. Importantly, NKILA is essential to prevent over-activation of NF-kB pathway in inflammation-stimulated breast epithelial cells. Furthermore, low NKILA expression is associated with breast cancer metastasis and poor patient prognosis. Therefore, lncRNAs can directly interact with functional domains of signaling proteins, serving as a class of NF-kB modulators to suppress cancer metastasis.
A Cytoplasmic NF-kB Interacting Long Noncoding RNA Blocks IkB Phosphorylation and Suppresses Breast Cancer Metastasis
Figure 3. NKILA Inhibits IkB Phosphorylation by Interacting with thenf-kb:IkB Complex (A) Western Blotting showing total and phosphorylated IKK and IkBa in MDAMB-231 or MCF7. (B) western blotting showing total and phosphorylated proteins of IKK andIkBa in TNF-a-treated MDA-MB-231 cells. (C) Confocal FISH images showing colocalization of NKILA and p65 in MCF7. (D) Binding of NKILA to p65/p50/IkBa complex in MCF7 cells, shown by RNA immunoprecipitation and qRT-PCR (mean ± SD, n = 3, **p < 0.01, ***p < 0.001 versus IgG). (E) In vitro interaction between NKILA and p65, p50, or IkBa, shown by RNA pull down. (F) Western blot analysis for phosphorylated and total IkBa in NKILA-expressing MDA-MB-231 cells treated with TNF-a and transfected with sirnastargeting p65 (GFP-si, GFP siRNA; p65-si1, 2, p65 siRNA1, 2).

原文链接:http://www.cell.com/cancer-cell/abstract/S1535-6108(15)00054-9
 
作者:广州赛诚生物 点击:
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