Phosphorylation of NF-κB by calmodulin-dependent kinase IV activates anti-apoptotic gene expression
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.
Available from: Stefka Mincheva-Tasheva
- "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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ABSTRACT: Intracellular pathways related to cell survival regulate neuronal physiology during development and neurodegenerative disorders. One of the pathways that have recently emerged with an important role in these processes is nuclear factor-κB (NF-κB). The activity of this pathway leads to the nuclear translocation of the NF-κB transcription factors and the regulation of anti-apoptotic gene expression. Different stimuli can activate the pathway through different intracellular cascades (canonical, non-canonical, and atypical), contributing to the translocation of specific dimers of the NF-κB transcription factors, and each of these dimers can regulate the transcription of different genes. Recent studies have shown that the activation of this pathway regulates opposite responses such as cell survival or neuronal degeneration. These apparent contradictory effects depend on conditions such as the pathway stimuli, the origin of the cells, or the cellular context. In the present review, the authors summarize these findings and discuss their significance with respect to survival or death in the nervous system.
The Neuroscientist 07/2012; 19(2). DOI:10.1177/1073858412444007 · 6.84 Impact Factor
Available from: Ángeles Martín-Requero
- "NF-B/Rel proteins are primarily regulated by subcellular location, being kept in the cytoplasm by IB and released into the nucleus upon cellular stimulation . However, increasing evidence indicates that NF-B is also regulated by other mechanisms such as phosphorylation and interaction with other proteins  . CaM could modify the NF-B activity not only indirectly through CaM-dependent kinases and phosphatases  , but also directly through interaction of CaM with NF-B/Rel proteins . "
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ABSTRACT: Cell cycle disturbances may precede neuronal death in Alzheimer's disease (AD). We described alterations, in lymphocytes from AD patients, on the activity of two transcription factors, E2F and NF-kappaB, involved in cell proliferation and survival regulation, demonstrating that cell cycle dysfunction also occurs in peripheral cells. The analysis of E2F-DNA binding activity revealed lower signal intensity of protein-DNA complexes in AD cells, which correlated with increased phosphorylation of retinoblastoma (pRb) related proteins and enhanced proliferation. The calmodulin (CaM) antagonist calmidazolium (CMZ) abrogated the increased activity of AD cells by partially dephosphorylating pRb and p130. The NF-kappaB-DNA binding activity increased as cell progress through the cell cycle. The reduced NF-kappaB activation observed in AD cells appears not to be related to the increased phosphorylation of the pRb family proteins nor with the enhanced proliferative activity of AD cells, but seems to protect them from death induced by the loss of trophic support. Ca2+/CaM antagonists rescue NF-kappaB-DNA binding activity and sensitize AD cells to serum withdrawal. These observations suggest that disruption of Ca2+/CaM signaling pathway could be linked mechanistically to its pro cell survival actions, promoting enhanced proliferation or decreased cell death depending on the presence of growth-stimulatory signals.
Neurobiology of Aging 06/2005; 26(5):615-24. DOI:10.1016/j.neurobiolaging.2004.06.006 · 5.01 Impact Factor
Available from: Jasmin Lalonde
- "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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ABSTRACT: Elevation of intracellular Ca2+ levels activates calcium/calmodulin-dependent protein kinase (CaMK) IV, which in turn plays an important role in neuroprotection and neuroplasticity. The possibility that CaMKIV is similarly involved in neocortical tissue has not been examined previously, especially with regard to the plastic nature of ocular dominance features in the primary visual cortex (area V1). We addressed this question by way of monocular enucleation (ME) to disrupt sensory input and examine CaMKIV expression changes in monkey area V1. Immunohistochemical staining of area V1 in normal infants showed a nuclear presence of CaMKIV, which did not changed after ME. However, a striking set of layer- and time-dependent changes in nuclear CaMKIV expression was observed in adult area V1 after ME. A strong increase in nuclear CaMKIV levels was evident in cortical layers II/III and VI after 1 d of ME and in layer IVC after 5 d of ME. These specific laminar changes persisted after 30 d of ME and, most notably, showed a columnar profile in which CaMKIV expression was linked to open-eye columns. Real-time quantitative reverse transcription-PCR and Western blot analysis showed that total amounts of CaMKIV mRNA and protein remained unchanged after ME, suggesting that a nuclear translocation may occur from the cytoplasm. Finally, double-label immunohistochemical staining with a pyramidal cell marker (SMI-32) showed that CaMKIV was absent in this subtype, whereas coincidental expression with GABA, parvalbumin, and calretinin, but not calbindin, showed its clear presence in a subset of interneurons. We propose that CaMKIV activity within diverse groups of cortical interneurons may play an important role in adaptive plastic reorganization of adult neocortical tissue.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2004; 24(2):554-64. DOI:10.1523/JNEUROSCI.1668-03.2004 · 6.34 Impact Factor
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