Phosphorylation of NF-κB by calmodulin-dependent kinase IV activates anti-apoptotic gene expression

Department of Molecular Biology, Pusan National University, Pusan 609-735, Republic of Korea.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 07/2003; 305(4):1094-8. DOI: 10.1016/S0006-291X(03)00869-6
Source: PubMed


We previously presented that calmodulin-dependent kinase IV (CaMKIV) mutually interacts with NF-kappa B and phosphorylates it directly, inducing the increased transcriptional regulation dependent on NF-kappa B target genes [J. Biol. Chem. 276 (2001) 20005]. Here, we show that Ser(535) residue is phosphorylated by CaMKIV. S535A mutant of p65 was specifically defective in transactivation of NF-kappa B target gene expression induced by CaMKIV. While coexpression of active CaMKIV with wild-type p65 led to a recovery from etoposide-induced apoptosis and an increase of Bcl-2 protein in cells, cells expressing S535A mutant did not. Taken together these results suggest that phosphorylated NF-kappa B p65 on Ser(535) by CaMKIV increases NF-kappa B target gene expression, including anti-apoptotic gene, hence leading to inhibition of apoptosis.

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    • "Otherwise, Ser311 phosphorylation of the RHD by PKCξ regulates CBP and RelA interaction (Duran and others 2003). Within the TAD domain there are several serine residues susceptible to phosphorylation by kinases: Ser468 phosphorylation occurs predominantly within the nucleus and is induced by the GSK-3b kinase (Buss and others 2004; Schwabe and Brenner 2002); Ser529 is phosphorylated by the CKII kinase when RelA is liberated from the IκBα inhibitor in response to IL-1 or TNF-α (Wang and others 2000); Ser535 can be phosphorylated by CAMKIV (Bae and others 2003) and Ser536 by IKKs in response to cytokines and mediated by the PI 3-kinase/ Akt pathway (Gutierrez and others 2008; Sizemore and others 2002). "
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    • "NF-␬B/Rel proteins are primarily regulated by subcellular location, being kept in the cytoplasm by I␬B and released into the nucleus upon cellular stimulation [4]. However, increasing evidence indicates that NF-␬B is also regulated by other mechanisms such as phosphorylation and interaction with other proteins [3] [21]. CaM could modify the NF-␬B activity not only indirectly through CaM-dependent kinases and phosphatases [1] [2], but also directly through interaction of CaM with NF-␬B/Rel proteins [2]. "
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    • "CaMKIV - mediated activity is known to play a role in neuropro - tection ( Bae et al . , 2003 ; Sée et al . , 2001 ) as well as in neuroplastic events associated with late phase LTD , LTP , and consolidation / retention of memory ( Ho et al . , 2000 ; Kang et al . , 2001 ; Wei et al . , 2002 ) . A clue as to how CaMKIV may be involved in these func - tions can be taken from its role in mediating calcium - induced dendritic growt"
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