Abstract
Nuclear factor-κB (NF-κB) has a vital role in cell survival. Inhibition of NF-κB has been proven to be an efficient therapeutic pathway for various cancers. Activation of NF-κB is mainly through serine residues' phosphorylation of inhibitor of κBα (IκBα) by IKK complex. Phosphorylation at tyrosine 42 is an alternative pathway in regulation of IκBα and NF-κB signaling, though little is known about the underlying mechanism. Here we identified regulator of calcineurin 1 (RCAN1) as a novel endogenous inhibitor of NF-κB signaling pathway. RCAN1 can interact with IκBα and affect the phosphorylation of IκBα at tyrosine 42. Overexpression of RCAN1 by adenovirus reduced cell viability in lymphoma Raji cells and restrained the growth of lymphoma transplants in mice. We further found that N terminus 1–103aa of RCAN1 is sufficient to inhibit NF-κB and reduce cell viability of lymphoma cells. Our study implicated a novel therapeutic approach for lymphoma by RCAN1 through inhibition of NF-κB signaling.
Highlights
ΚB is an important regulator of cell survival, proliferation and differentiation.[1]
To investigate whether regulator of calcineurin 1 (RCAN1) has an effect on Nuclear factor-κB (NF-κB) activity, RCAN1 expression plasmids pRCAN1.1mychis and pRCAN1.4mychis were co-transfected with reporter pNF-κBLuc into HEK293 cells
Our data here showed that RCAN1 affected inhibitor of κBα (IκBα) Y42 phosphorylation
Summary
ΚB is an important regulator of cell survival, proliferation and differentiation.[1]. Binding domain termed Rel homology region that enables them to form various homo- or hetero-dimeric complexes.[7]. An alternative mechanism for NF-κB activation involves the phosphorylation of tyrosine (Y) residue 42 of IκBα, with or without inducing its degradation.[9,10] Though there were extensive studies in the serine phosphorylation by IKK complex, little is known about the regulation of IκBα Y42 phosphorylation that affects NF-κB signaling. RCAN1 inhibits calcineurin–nuclear factor of activated T-cell (NFAT) pathway in vitro and in vivo by interacting with calcineurin subunit A via its C-terminal 140–197aa.[11] NFAT can activate RCAN1 isoform 4 gene expression via several responsive elements in the promoter region of − 350–166 bp,[12,13] forming a negative feedback loop. A single extra copy of RCAN1 is sufficient to suppress tumor angiogenesis in mice.[15]
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