Activation of the Protein Kinase A Increases the DNA‐Binding and Transcriptional Activity of c‐Rel in T Cells

Abstract

Cyclic AMP (cAMP)-dependent protein kinase A (PKA) is known to have both negative and positive effects on the activation mechanisms of T lymphocytes. The authors have analysed the effect of increased cAMP on the activation of NF-kappa B transcription factor. This factor controls the expression of several genes (e.g. IL-2 and IL-2 receptor) involved in the activation and proliferation of T cells. The authors found that elevation of intracellular cAMP in Jurkat T leukaemia cells activated with phorbol ester (PDBu)/calcium ionophore (A23187) increased the DNA-binding of NF-kappa B as detected by the electrophoretic mobility shift assay (EMSA). Analysis of the subunit composition of the DNA-binding complex indicated that the amount of c-Rel was enhanced while RelA was decreased. Analysis of the effect of elevated cAMP on the degradation of I kappa B-alpha and I kappa B-beta did not reveal an essential change in degradation kinetics of these inhibitor proteins. The elevation of cAMP did not increase the synthesis of c-Rel, but it enhanced the nuclear localization of this protein. Transfection of Jurkat cells with a plasmid kB/TK10-CAT indicated that the increased DNA-binding of c-Rel containing complexes seen in EMSA was also functional. These data imply that the strong and long-lasting c-Rel nuclear localization and DNA-binding induced by protein kinase A is not due to increased c-Rel synthesis or enhanced degradation of the I kappa B inhibitors. Therefore, a direct phosphorylation of the c-Rel protein is the most plausible explanation for these observations. Taken together, these results suggest that cAMP is able to regulate the expression of NF-kappa B-dependent genes in T cells by modifying the composition and subunit activity of NF-kappa B.

Roles of p38 Mitogen-Activated Protein Kinase, NF-κB, and Protein Kinase C in Proinflammatory Cytokine mRNA Expression by Human Peripheral Blood Leukocytes, Monocytes, and Neutrophils in Response toAnaplasma phagocytophila

“…NF-B activation by LPS has also been reported to be PTK dependent (13,46,50), suggesting that A. phagocytophila may share with LPS the same PTK-dependent pathway upstream of p38 MAPK activation. PKA activation was reported to increase DNA binding of NF-B in T cells (22), and PKA activates p38 MAPK in endocrine cells (41). The overall responses of PBLs and monocytes were similar in the present study.…”

Depression, social support, and beta-adrenergic transcription control in human ovarian cancer

“…Studies in in vitro model systems suggest that beta-adrenergic signaling can also activate NF-κB/Rel-family transcription factors, although these effects are variable across cell type and experimental conditions (Shirakawa and Mizel 1989;Lahdenpohja, Henttinen et al 1996;Zhong, Voll et al 1998;Bierhaus, Wolf et al 2003;Richlin, Arevalo et al 2004). In secondary analyses examining the distribution of cRel (cRel/p50 heterodimer) and RelA (p65/p50 heterodimer) promoter motifs, the prevalence of V$CREL_01 TFBMs was 3.7-fold higher in genes over-expressed in tumors from high-risk patients relative to low-risk patients (mean = .…”

“…PKA regulates gene expression by phosphorylating multiple transcription factors, including members of the cAMP response element binding protein / activating transcription factor (CREB/ATF) family (Montminy 1997). Under certain circumstances, PKA can also cross-regulate activity of the proinflammatory NF-κB/Rel family of transcription factors (Shirakawa and Mizel 1989;Lahdenpohja, Henttinen et al 1996;Zhong, Voll et al 1998;Bierhaus, Wolf et al 2003;Richlin, Arevalo et al 2004), the pro-inflammatory STAT family of transcription factors (Landen, Lin et al 2007), and the growth-promoting Ets transcription factors (Janknecht, Monte et al 1996;Vossler, Yao et al 1997;Luttrell, Ferguson et al 1999;Wu and Janknecht 2002), providing multiple signaling pathways for functional genomic regulation by catecholamines.…”

Regulation of c-Rel Nuclear Localization by Binding of Ca2+/Calmodulin

“…NF-B/Rel proteins are themselves phosphorylated upon cellular stimulation (4,17,34,37,40,45,46,56,57,66,67). Stimulationinduced phosphorylation of the transactivation domains of RelA and c-Rel enhances their ability to activate transcription.…”

“…NF-B1 has also been shown to become phosphorylated in response to stimulation, resulting in a more stable interaction with DNA (37). In addition, there is evidence that the cAMPdependent protein kinase PKA regulates c-Rel activity (34,45). The outcome of activation of NF-B/Rel proteins also depends on their interaction with other proteins.…”