Phosphorylation of NF-kappa B by calmodulin-dependent kinase IV activates anti-apoptotic gene expression.
ABSTRACT 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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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; DOI:10.1177/1073858412444007 · 7.62 Impact Factor
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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 · 4.85 Impact Factor
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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 · 6.75 Impact Factor