Ceramide and Cyclic Adenosine Monophosphate (cAMP) Induce cAMP Response Element Binding Protein Phosphorylation via Distinct Signaling Pathways While Having Opposite Effects on Myeloid Cell Survival

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 217-225 ◽  
Author(s):  
Michael P. Scheid ◽  
Ian N. Foltz ◽  
Peter R. Young ◽  
John W. Schrader ◽  
Vincent Duronio
Keyword(s):  
P38 Mapk ◽  
Binding Protein ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Camp Response Element Binding ◽  
Camp Response Element ◽  
Response Element ◽  
Creb Phosphorylation ◽  
Element Binding Protein ◽  
Induced Apoptosis

Abstract The role of ceramide as a second messenger is a subject of great interest, particularly since it is implicated in signaling in response to inflammatory cytokines. Ceramide induces apoptosis in both cytokine-dependent MC/9 cells and factor-independent U937 cells. Elevation of cyclic adenosine monophosphate (cAMP) levels inhibits apoptosis induced by ceramide and several other treatments. One target of cAMP-mediated signaling is the transcription factor CREB (cAMP response element binding protein), and recently CREB phosphorylation at an activating site has been shown to also be mediated by a cascade involving p38 mitogen-activated protein kinase (MAPK), one of the stress-activated MAP kinases. Because no role for p38 MAPK in apoptosis has been firmly established, we examined the relationship between p38 MAPK and CREB phosphorylation under various conditions. Ceramide, or sphingomyelinase, like tumor necrosis factor- (TNF-) or the hematopoietic growth factor, interleukin-3 (IL-3), was shown to activate p38 MAPK, which in turn activated MAPKAP kinase-2. Each of these treatments led to phosphorylation of CREB (and the related factor ATF-1). A selective p38 MAPK inhibitor, SB203580, blocked TNF-– or ceramide-induced CREB phosphorylation, but had no effect on the induction of apoptosis mediated by these agents. The protective agents cAMP and IL-3 also led to CREB phosphorylation, but this effect was independent of p38 MAPK, even though IL-3 was shown to activate both p38 MAPK and MAPKAP kinase-2. Therefore, the opposing effects on apoptosis observed with cAMP and IL-3, compared with ceramide and TNF-, could not be explained on the basis of phosphorylation of CREB. In addition, because SB203580 had no effect of TNF- or ceramide-induced apoptosis, our results strongly argue against a role for p38 MAPK in the induction of TNF-– or ceramide-induced apoptosis.

Ceramide and Cyclic Adenosine Monophosphate (cAMP) Induce cAMP Response Element Binding Protein Phosphorylation via Distinct Signaling Pathways While Having Opposite Effects on Myeloid Cell Survival

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 217-225 ◽  
Author(s):  
Michael P. Scheid ◽  
Ian N. Foltz ◽  
Peter R. Young ◽  
John W. Schrader ◽  
Vincent Duronio
Keyword(s):  
P38 Mapk ◽  
Binding Protein ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Camp Response Element Binding ◽  
Camp Response Element ◽  
Response Element ◽  
Creb Phosphorylation ◽  
Element Binding Protein ◽  
Induced Apoptosis

The role of ceramide as a second messenger is a subject of great interest, particularly since it is implicated in signaling in response to inflammatory cytokines. Ceramide induces apoptosis in both cytokine-dependent MC/9 cells and factor-independent U937 cells. Elevation of cyclic adenosine monophosphate (cAMP) levels inhibits apoptosis induced by ceramide and several other treatments. One target of cAMP-mediated signaling is the transcription factor CREB (cAMP response element binding protein), and recently CREB phosphorylation at an activating site has been shown to also be mediated by a cascade involving p38 mitogen-activated protein kinase (MAPK), one of the stress-activated MAP kinases. Because no role for p38 MAPK in apoptosis has been firmly established, we examined the relationship between p38 MAPK and CREB phosphorylation under various conditions. Ceramide, or sphingomyelinase, like tumor necrosis factor- (TNF-) or the hematopoietic growth factor, interleukin-3 (IL-3), was shown to activate p38 MAPK, which in turn activated MAPKAP kinase-2. Each of these treatments led to phosphorylation of CREB (and the related factor ATF-1). A selective p38 MAPK inhibitor, SB203580, blocked TNF-– or ceramide-induced CREB phosphorylation, but had no effect on the induction of apoptosis mediated by these agents. The protective agents cAMP and IL-3 also led to CREB phosphorylation, but this effect was independent of p38 MAPK, even though IL-3 was shown to activate both p38 MAPK and MAPKAP kinase-2. Therefore, the opposing effects on apoptosis observed with cAMP and IL-3, compared with ceramide and TNF-, could not be explained on the basis of phosphorylation of CREB. In addition, because SB203580 had no effect of TNF- or ceramide-induced apoptosis, our results strongly argue against a role for p38 MAPK in the induction of TNF-– or ceramide-induced apoptosis.

scholarly journals Update and Potential Opportunities in CBP [Cyclic Adenosine Monophosphate (cAMP) Response Element-Binding Protein (CREB)-Binding Protein] Research Using Computational Techniques

2021 ◽  
Vol 40 (1) ◽  
pp. 19-27
Author(s):  
Oluwayimika E. Akinsiku ◽  
Opeyemi S. Soremekun ◽  
Mahmoud E. S. Soliman
Keyword(s):  
Inflammatory Diseases ◽  
Binding Protein ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Camp Response Element Binding ◽  
Computational Techniques ◽  
Creb Binding Protein ◽  
Camp Response Element ◽  
Response Element ◽  
Element Binding Protein

AbstractCBP [cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB)-binding protein] is one of the most researched proteins for its therapeutic function. Several studies have identified its vast functions and interactions with other transcription factors to initiate cellular signals of survival. In cancer and other diseases such as Alzheimer’s, Rubinstein-taybi syndrome, and inflammatory diseases, CBP has been implicated and hence an attractive target in drug design and development. In this review, we explore the various computational techniques that have been used in CBP research, furthermore we identified computational gaps that could be explored to facilitate the development of highly therapeutic CBP inhibitors.

scholarly journals Cyclic AMP response element-binding protein is required in excitatory neurons in the forebrain to sustain wakefulness

SLEEP ◽  
2020 ◽  
Author(s):  
Mathieu E Wimmer ◽  
Rosa Cui ◽  
Jennifer M Blackwell ◽  
Ted Abel
Keyword(s):  
Cyclic Amp ◽  
Intracellular Signaling ◽  
Target Genes ◽  
Binding Protein ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Response Element ◽  
Creb Phosphorylation ◽  
Element Binding Protein ◽  
And Control

Abstract The molecular and intracellular signaling processes that control sleep and wake states remain largely unknown. A consistent observation is that the cyclic adenosine monophosphate (AMP) response element-binding protein (CREB), an activity-dependent transcription factor, is differentially activated during sleep and wakefulness. CREB is phosphorylated by the cyclic AMP/protein kinase A (cAMP/PKA) signaling pathway as well as other kinases, and phosphorylated CREB promotes the transcription of target genes. Genetic studies in flies and mice suggest that CREB signaling influences sleep/wake states by promoting and stabilizing wakefulness. However, it remains unclear where in the brain CREB is required to drive wakefulness. In rats, CREB phosphorylation increases in the cerebral cortex during wakefulness and decreases during sleep, but it is not known if this change is functionally relevant to the maintenance of wakefulness. Here, we used the Cre/lox system to conditionally delete CREB in the forebrain (FB) and in the locus coeruleus (LC), two regions known to be important for the production of arousal and wakefulness. We used polysomnography to measure sleep/wake levels and sleep architecture in conditional CREB mutant mice and control littermates. We found that FB-specific deletion of CREB decreased wakefulness and increased non-rapid eye movement sleep. Mice lacking CREB in the FB were unable to sustain normal periods of wakefulness. On the other hand, deletion of CREB from LC neurons did not change sleep/wake levels or sleep/wake architecture. Taken together, these results suggest that CREB is required in neurons within the FB but not in the LC to promote and stabilize wakefulness.

scholarly journals A Novel Cell-Based Assay for G-Protein-Coupled Receptor-Mediated Cyclic Adenosine Monophosphate Response Element Binding Protein Phosphorylation

2006 ◽  
Vol 11 (4) ◽  
pp. 351-358 ◽  
Author(s):  
Julie V. Selkirk ◽  
Lisa M. Nottebaum ◽  
Ian C. Ford ◽  
Mark Santos ◽  
Siobhan Malany ◽  
...  
Keyword(s):  
G Protein ◽  
Binding Protein ◽  
Expression System ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
G Protein Coupled Receptor ◽  
Response Element ◽  
Creb Phosphorylation ◽  
Element Binding Protein ◽  
G Protein Coupled

Currently, the most popular means of assessing functional activity of Gs/olf-coupled receptors is via the measurement of intracellular cyclic adenosine monophosphate (cAMP) accumulation. An additional readout is the downstream phosphorylation of cAMP response element binding protein (CREB), which gives an indication of gene transcription, the ultimate response of many G-protein-coupled receptor (GPCR) signals. Current methods of quantifying CREB phosphorylation are low throughput, and so we have designed a novel higher throughput method using the Odyssey™ infrared imaging system. Functional potencies of both agonists and antagonists correlate well with radioligand binding affinities determined using examples of both an endogenous (adenosine2A receptor in PC-12 cells) and a heterologous (human melanocortin 4 receptor in HEK-293 cells) expression system. For example, the antagonist ZM241385 demonstrates 0.23 ± 0.03 nM affinity for the A2A receptor and has a functional potency of 0.26 ± 0.04 nM determined using cAMP and 0.15 ± 0.06 nM using CREB phosphorylation. These data demonstrate that this novel approach for the measurement of CREB phosphorylation is a useful tool for the assessment of GPCR activity in whole cells and is more amenable to the throughput required for the purposes of drug discovery.

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