<scp>DAX</scp>‐1

Lalli, Enzo; Sassone–Corsi, Paolo

doi:10.1002/0471203076.emm0814

Cited by 12 publications

(24 citation statements)

References 21 publications

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“…Conversely, the effect of elongation or dissociation on activity in cyclic nucleotide-dependent protein kinases is currently unknown. Although binding of cAMP was originally assumed to cause dissociation of the R and C subunits in PKA (27)(28)(29), fluorescent resonance energy transfer measurements suggest that dissociation may require interactions with the PKA inhibitor protein (30)(31)(32)(33), and question whether dissociation is required for activation (34,35). Under the conditions used here for ⌬ 1-52 PKG-I␤, and in our previous study of PKG-I␣ (11), we found that cGMP binding was sufficient to induce both elongation and activation.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms associated with cGMP binding and activation of cGMP-dependent protein kinase

Wall

Francis

Corbin

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Using small-angle x-ray scattering, we have observed the cGMPinduced elongation of an active, cGMP-dependent, monomeric deletion mutant of cGMP-dependent protein kinase (⌬ 1-52 PKG-I␤). On saturation with cGMP, the radius of gyration of ⌬ 1-52 PKG-I␤ increases from 29.4 ؎ 0.1 Å to 40.1 ؎ 0.7 Å, and the maximum linear dimension increases from 90 Å ؎ 10% to 130 Å ؎ 10%. The elongation is due to a change in the interaction between structured regulatory (R) and catalytic (C) domains. A model of cGMP binding to ⌬ 1-52 PKG-I␤ indicates that elongation of ⌬ 1-52 PKG-I␤ requires binding of cGMP to the low-affinity binding site of the R domain. A comparison with cAMP-dependent protein kinase suggests that both elongation and activation require cGMP binding to both sites; cGMP binding to the low-affinity site therefore seems to be a necessary, but not sufficient, condition for both elongation and activation of ⌬ 1-52 PKG-I␤. We also predict that there is little or no cooperativity in cGMP binding to the two sites of ⌬ 1-52 PKG-I␤ under the conditions used here. Results obtained by using the ⌬ 1-52 PKG-I␤ monomer indicate that a previously observed elongation of PKG-I␣ is consistent with a pure change in the interaction between the R domain and the C domain, without alteration of the dimerization interaction. This study has revealed important features of molecular mechanisms in the biochemical network describing PKG-I␤ activation by cGMP, yielding new insight into ligand activation of cyclic nucleotide-dependent protein kinases, a class of regulatory proteins that is key to many cellular processes.C yclic guanosine monophosphate (cGMP) is a second messenger signaling molecule that is central to the regulation of many physiological processes, including smooth muscle tone, visual transduction, platelet aggregation, bone growth, and electrolyte and fluid homeostasis (see reviews in refs. 1-3). Its known targets are ion channels, which can alter cellular cation or anion transport; phosphodiesterases, which degrade cyclic nucleotides; and the cGMP-dependent protein kinases (PKGs), which are believed to be responsible for most intracellular cGMP actions. The PKG [first discovered by Kuo and Greengard (4)] is a serine͞threonine protein kinase whose substrates include ion channels and pumps, receptors, and enzymes that control intracellular Ca 2ϩ concentrations. In its active form, PKG can transfer the ␥-phosphate from ATP to target proteins, preferentially targeting serines in substrates having consensus sequence RRXSX, with some exceptions (1, 5). Phosphorylation of target proteins by PKG effects smooth muscle relaxation by reduction of cellular Ca 2ϩ . The PKGs and cAMP-dependent protein kinases (PKA) are homologous enzymes, and the two enzyme families share many similarities in biochemical function and domain organization.PKG is a dimer comprised of two identical monomers (1-3). Each monomer of PKG contains a regulatory domain (R) and a catalytic domain (C) on a single polypeptide chain. The monomers dimerize via interactions ...

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Section: Discussionmentioning

confidence: 99%

Mechanisms associated with cGMP binding and activation of cGMP-dependent protein kinase

Wall

Francis

Corbin

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…ICER Represses CREB and AP-1-regulated Transactivation of Cathelicidin-CREB and AP-1 are mainly activated by phosphorylation, whereas dephosphorylation remains the major counter-regulatory mechanism that controls expression of genes induced by them (46,57). However, considerable CREB phosphorylation persisted after 6 h of stimulation of the HT-29 cells with FSK, whereas basal cathelicidin expression level was restored (supplemental Fig.…”

Section: Camp Regulates Cathelicidin Expression In the Epithelialmentioning

confidence: 98%

“…S2). Some of the CREB and AP-1 regulated genes are known to be counter-regulated by an inducible repressor called ICER (45,46,58). We had earlier reported that cathelicidin and ICER expression in the NaB-differentiated HT-29 cells bears an inverse relation (43).…”

Section: Camp Regulates Cathelicidin Expression In the Epithelialmentioning

confidence: 99%

“…Protein kinase A (PKA) is the best known cAMP effector that regulates transcription mainly through direct phosphorylation and activation of the bZip family members CREB, CREM , and ATF1. Activated bZip family transcription factors bind the consensus cAMP-response element (CRE) sequences over the promoters of the cAMP-responsive genes (45,46). A similar sequence called AP-1-response element/TPA-response element (ARE/ TRE) is occupied by activated AP-1 family proteins c-Fos and c-Jun.…”

mentioning

confidence: 99%

“…CRE-and ARE/TRE-binding factors also include several transcriptional repressors. Although the majority of them (CREM␣, -␤, and -␥, E4BP4, and CREB2) are regulated via phosphorylation by PKA, a group of CREM family members known as ICER is stringently controlled at the transcriptional level by CREB and an autoregulatory feedback mechanism (45,46). Our previous studies have suggested that ICER may be involved in the transcriptional repression of cathelicidin (43).…”

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confidence: 99%

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cAMP Stringently Regulates Human Cathelicidin Antimicrobial Peptide Expression in the Mucosal Epithelial Cells by Activating cAMP-response Element-binding Protein, AP-1, and Inducible cAMP Early Repressor

Chakraborty

Maity

Sil

et al. 2009

Journal of Biological Chemistry

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Little is known about the regulation of the innate host defense peptide cathelicidin at the mucosal surfaces. Expression is believed to be transcriptionally regulated, and several cis-acting elements have been identified in the cathelicidin putative promoter. However, the trans-acting factors have not been clearly defined. We have recently reported that bacterial exotoxins suppress cathelicidin expression in sodium butyrate-differentiated intestinal epithelial cells (ECs), and this may be mediated through inducible cAMP early repressor. Here we have shown that cAMP-signaling pathways transcriptionally regulate cathelicidin expression in various ECs. cAMP-response elementbinding protein (CREB) and AP-1 (activator protein-1) bind to the cathelicidin putative promoter in vitro. Additionally, transcriptional complexes containing CREB, AP-1, and cathelicidin upstream regulatory sequences are formed within ECs. We have also shown that these complexes may activate cathelicidin promoter and are required for its inducible expression in ECs. This is underscored by the fact that silencing of CREB and AP-1 results in failure of ECs to up-regulate cathelicidin, and hepatitis B virus X protein may use CREB to induce cathelicidin. On the other hand, inducible cAMP early repressor competes with CREB and AP-1 for binding to the cathelicidin promoter and represses transcription, thus functioning as a counter-regulatory mechanism. Finally, both CREB and AP-1 were shown to play major roles in the regulation of cathelicidin in sodium butyrate-differentiated HT-29 cells. This is the first report of a detailed mechanistic study of inducible cathelicidin expression in the mucosal ECs. At the same time, it describes a novel immunomodulatory function of cAMP.

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Modulation of HIV‐1 enhancer activity and virus production by cAMP

et al. 2001

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The effect of cAMP on the transcriptional activity of the HIV-1 long terminal repeat/enhancer was investigated and compared to the effect of cAMP on virus replication. In culture cAMP repressed virus replication in vivo using different cell types. Transient transfection studies with HIV-1 enhancerderived luciferase reporter gene constructs identified the minimal DNA sequence mediating the negative regulatory effect of cAMP on HIV-1 transcription. A single nuclear factor U UB element from the HIV-1 enhancer mediates the repressive effect on transcription. AP-2 is not involved in cAMP repression. Stable transfection of Jurkat T cells with the co-activators CREB binding protein (CBP) and p300 completely abolished the cAMP repressive effect, supporting the hypothesis that elevation of intracellular cAMP increases phosphorylation of CREB, which then competes with phosphorylated p65 and Ets-1 for limiting amounts of CBP/p300 thereby mediating the observed repressive effect on transcription. These findings suggest an important role of cAMP on HIV-1 transcription. ß

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DAX‐1

Cited by 12 publications

References 21 publications

Mechanisms associated with cGMP binding and activation of cGMP-dependent protein kinase

Mechanisms associated with cGMP binding and activation of cGMP-dependent protein kinase

cAMP Stringently Regulates Human Cathelicidin Antimicrobial Peptide Expression in the Mucosal Epithelial Cells by Activating cAMP-response Element-binding Protein, AP-1, and Inducible cAMP Early Repressor

Modulation of HIV‐1 enhancer activity and virus production by cAMP

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