Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p50 subunit of NF-kappa B is derived from the amino terminus of a 105 kilodalton precursor. The p105 carboxyl terminus, which contains ankyrin-like repeats, a feature of I kappa B molecules, regulates the cytoplasmic retention of p105 and inhibits DNA binding by the precursor. Here, we describe an I kappa B protein identical to the carboxyl-terminal region of p105. Probes spanning the COOH terminus but not the rel homology domain of p105 hybridize to a distinct 2.6-kilobase mRNA expressed in a wide range of murine tissues. The nucleotide sequence of complementary DNA clones for this transcript, in vitro translation, and immune precipitation of metabolically labeled cell lysates establish that it encodes a 70 kilodalton protein that corresponds to the COOH-terminal 607 amino acids of p105. p70 suppresses p65 and p75c-rel mediated transactivation of reporter genes under the control of NF-kappa B elements and in vitro can prevent DNA binding of p50 and p75c-rel homodimers to NF-kappa B sites. The ability of p70 to stably associate with p49 and p65 in vitro, but not inhibit DNA binding by these proteins, suggests that the specific inhibitory properties of this I kappa B may reflect its relative affinity for different rel targets. p70 phosphorylated by protein kinase A fails to inhibit DNA binding by p50 or the c-rel protein, and sequencing of radiolabeled p70 tryptic phosphopeptides establishes that protein kinase A phosphorylates serine residue 576 of p70. This finding suggests that the inhibitory activity of p70 can be regulated by signaling via the adenylate cyclase pathway.
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PMID:The activity of a 70 kilodalton I kappa B molecule identical to the carboxyl terminus of the p105 NF-kappa B precursor is modulated by protein kinase A. 839 3

Incubating 3T3-L1 adipocytes with forskolin, which increases intracellular cAMP by activating adenylate cyclase, mimicked rapamycin by attenuating the effect of insulin on stimulating the phosphorylation of four (S/T)P sites in PHAS-I, a downstream target of the mammalian target of rapamycin (mTOR) signaling pathway. To investigate the hypothesis that increasing cAMP inhibits mTOR, the protein kinase activity of mTOR was measured in an immune complex assay with recombinant PHAS-I as substrate. Both forskolin and 8-(4-chlorophenylthio)adenosine 3'-5'-monophosphate (CPT-cAMP) prevented the activation of mTOR by insulin in adipocytes, but neither agent affected mTOR activity when added directly to the immunopurified protein. In contrast, the cAMP phosphodiesterase inhibitor, theophylline, inhibited mTOR activity not only when added to intact adipocytes but also when added to immunopurified mTOR in vitro, demonstrating that certain methylxanthines are able to inhibit mTOR independently of increasing cAMP. Forskolin and CPT-cAMP blocked the effect of insulin on increasing mTOR phosphorylation, which was assessed using mTAb1, an antibody whose binding is inhibited by phosphorylation of mTOR. Although the mTAb1 epitope contains a consensus site for protein kinase B, neither agent inhibited the activation of protein kinase B produced by insulin. These findings support the interpretation that increasing cAMP attenuates the effects of insulin on PHAS-I, p70(S6K), and other downstream targets of the mTOR signaling pathway by inhibiting the phosphorylation and activation of mTOR.
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PMID:Attenuation of mammalian target of rapamycin activity by increased cAMP in 3T3-L1 adipocytes. 985 18

Our previous results show that recombinant gp41 (aa565-647), the extracellular domain of HIV-1 transmembrane glycoprotein, stimulates interleukin-10 (IL-10) production in human monocytes. The signal cascade transducing this effect is not yet clear. In this study, we examined whether gp41-induced IL-10 up-regulation is mediated by the previously described synergistic activation of cAMP and NF-kappaB pathways. gp41 induced cAMP accumulation in monocytes in a time- and concentration-dependent manner and the adenylate cyclase inhibitor SQ 22536 suppressed gp41-induced IL-10 production in monocytes. In contrast, gp41 failed to stimulate NF-kappaB binding activity in as much as no NF-kappaB bound to the main NF-kappaB-binding site 2 of the IL-10 promoter after addition of gp41. We also examined the involvement of other signal transduction pathways. Specific inhibitors of p70(S6)-kinase (rapamycin), and Gi protein (pertussis toxin), prevented induction of IL-10 production by gp41 in monocytes, while inhibitors of the phosphatidylinositol 3-kinase (PI 3-kinase) (wortmannin) and mitogen-activated protein kinase (MAPK) pathway (PD 98059) did not. Thus HIV-1 gp41-induced IL-10 up-regulation in monocytes may not involve NF-kappaB, MAPK, or PI 3-kinase activation, but rather may operate through activation of adenylate cyclase and pertussis-toxin-sensitive Gi/Go protein to effect p70(S6)-kinase activation.
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PMID:Involvement of adenylate cyclase and p70(S6)-kinase activation in IL-10 up-regulation in human monocytes by gp41 envelope protein of human immunodeficiency virus type 1. 1008 66

Bordetella pertussis, the causative agent of whooping cough, possesses an array of virulence factors, including adenylate cyclase toxin (ACT), relevant in the establishment of infection. Here we better define the impact of cyclic AMP (cAMP) intoxication due to the action of ACT on dendritic cell (DC)-driven immune response, by infecting monocyte-derived DC (MDDC) with an ACT-deficient B. pertussis mutant (ACT- 18HS19) or its parental strain (WT18323). Both strains induced MDDC maturation and antigen-presenting cell functions; however, only ACT- 18HS19 infected MDDC-induced production of interleukin-12 (IL-12) p70. Gene expression analysis of the IL-12 cytokine family subunits revealed that both strains induced high levels of p40 (protein chain communal to IL-12 p70 and IL-23) as well as p19, a subunit of IL-23. Conversely only ACT- 18HS19 infection induced consistent transcription of IL-12 p35, a subunit of IL-12 p70. Addition of the cAMP analogous D-butyril-cAMP (D-cAMP) abolished IL-12 p70 production and IL-12 p35 expression in ACT- 18HS19-infected MDDC. ACT- 18HS19 infection induced the expression of the transcription factors interferon regulatory factor 1 (IRF-1) and IRF-8 and of beta interferon, involved in IL-12 p35 regulation, and the expression of these genes was inhibited by D-cAMP addition and in WT18323-infected MDDC. The concomitant expression of IL-12 p70 and IL-23 allowed ACT- 18HS19 to trigger a more pronounced T helper 1 polarization compared to WT18323. The present study suggests that ACT-dependent cAMP induction leads to the inhibition of pathways ultimately leading to IL-12 p35 production, thus representing a mechanism for B. pertussis to escape the host immune response.
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PMID:Bordetella pertussis inhibition of interleukin-12 (IL-12) p70 in human monocyte-derived dendritic cells blocks IL-12 p35 through adenylate cyclase toxin-dependent cyclic AMP induction. 1662 21