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 effect of increased intracellular cAMP on MCF-7 breast cancer cell growth was examined by treating cells with either forskolin, an activator of adenylate cyclase, or 8-[4-chlorophenylthio]-cAMP (8-CPT-cAMP), a cAMP analog. Compared to cells maintained in control medium, treatment with either 1 or 10 microM forskolin decreased cell growth by 17% and 68%, respectively, whereas treatment with 250 microM 8-CPT-cAMP decreased cell growth by 29%. To determine whether this effect of cAMP on cell growth was mediated by inhibition of the activity of extracellular signal-regulated kinases 1 and 2 (ERK1 and -2), two mitogen-activated protein kinases, the effect of cAMP on growth factor-induced ERK activity in MCF-7 cells was examined. Treatment with either insulin-like growth factor I (IGF-I) or epidermal growth factor (EGF) for 10 min stimulated a 4- to 8-fold increase in ERK1 and -2 activity. This effect of IGF-I and EGF was not inhibited by increased intracellular cAMP generated by pretreatment of the cells with 10 microM forskolin. Similarly, 10 microM forskolin had no effect on IGF-I- or EGF-induced ERK activity in cells treated with growth factor for 30 min. To determine whether cAMP inhibits other growth factor-mediated effects, its effect on the activity of the serum response element (SRE), a DNA promoter element whose activity is regulated by a variety of growth-promoting events, was examined. For these assays, MCF-7 cells were transiently transfected with pTK81-SRE-Luc, a luciferase fusion gene that contains the SRE cloned 5' to a minimal thymidine kinase promoter and the luciferase gene. Treatment with either IGF-I or EGF increased pTK81-SRE-Luc activity in a dose-dependent fashion. Pretreatment of cells with 10 microM forskolin decreased IGF-I- and EGF-stimulated luciferase activity by approximately 75%. An intermediate effect was observed using 1 microM forskolin. When intracellular cAMP levels were increased using 8-CPT-cAMP, similar results were obtained. SRE activity is dependent upon the activation by phosphorylation of a ternary complex factor; included among the ternary complex factors is Elk-1. When MCF-7 cells were cotransfected with a vector that expresses a Gal4/Elk-1 fusion protein and UAS-TK-Luc, a plasmid that contains two Gal4 DNA recognition sites cloned 5' to a thymidine kinase promoter and the luciferase gene, treatment with forskolin partially inhibited the activation of Elk-1 by IGF-I and EGF. These data demonstrate that in MCF-7 breast cancer cells, cAMP has no effect on IGF-I- or EGF-induced ERK activity, but it inhibits growth factor-induced transcription. Taken together with the effects of cAMP on IGF-I- and EGF-induced Elk-1 activation, these data suggest that the effect of cAMP on SRE activity occurs distal to ERK activation, possibly via inhibition of an ERK-independent pathway. Finally, these data indicate that the effect of increased intracellular cAMP on breast cancer growth may be mediated through inhibition of specific growth factor-induced effects, including gene transcription.
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PMID:Growth factor-induced transcription via the serum response element is inhibited by cyclic adenosine 3',5'-monophosphate in MCF-7 breast cancer cells. 916 3

Three mouse models of Alzheimer's disease (AD) were used to assess changes in gene expression potentially critical to amyloid beta-peptide (Abeta)-induced neuronal dysfunction. One mouse model harbored homozygous familial AD (FAD) knock-in mutations in both, amyloid precursor protein (APP) and presenilin 1 (PS-1) genes (APP(NLh/NLh)/PS-1(P264L/P264L)), the other two models harbored APP over-expression of FAD mutations (Tg2576) with the PS-1 knock-in mutation at either one or two alleles. These mouse models of AD had varying levels of Abeta40 and Abeta42 and different latencies and rates of Abeta deposition in brain. To assess changes in gene expression associated with Abeta accumulation, the Affymetrix murine genome array U74A was used to survey gene expression in the cortex of these three models both prior to and following Abeta deposition. Altered genes were identified by comparing the AD models with age-matched control littermates. Thirty-four gene changes were identified in common among the three models in mice with Abeta deposition. Among the up-regulated genes, three major classes were identified that encoded for proteins involved in immune responses, carbohydrate metabolism, and proteolysis. Down-regulated genes of note included pituitary adenylate cyclase-activating peptide (PACAP), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor I receptor (IGF-IR). In young mice without detectable Abeta deposition, there were no regulated genes common among the three models, although 40 genes were similarly altered between the two Tg2576 models with the PS-1 FAD knock-in. Finally, changes in gene expression among the three mouse models of AD were compared with those reported in human AD samples. Sixty-nine up-regulated and 147 down-regulated genes were found in common with human AD brain. These comparisons across different genetic mouse models of AD and human AD brain provide greater support for the involvement of identified gene expression changes in the neuronal dysfunction and cognitive deficits accompanying amyloid deposition in mammalian brain.
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PMID:Comparative analysis of cortical gene expression in mouse models of Alzheimer's disease. 1592 7

Kit ligand (Kitl) is an important paracrine factor involved in the activation of primordial follicles from the quiescent pool and in the maintenance of meiotic arrest before germinal vesicle breakdown (GVBD). It has been reported that follicle-stimulating hormone (FSH) stimulates but luteinizing hormone (LH) suppresses the expression of Kitl in the granulosa cells in mammals. Considering that both gonadotropins signal in the follicle cells mainly by activating cyclic adenosine 3', 5'-monophosphate (cAMP) pathway, we are intrigued by how cAMP differentially regulates Kitl expression. In the present study, we demonstrated that both human chorionic gonadotropin (hCG) and pituitary adenylate cyclase activating polypeptide (PACAP) inhibited insulin-like growth factor I (IGF-I)-induced Akt phosphorylation and kitlga expression in the zebrafish follicle cells. Further experiments showed that cAMP was involved in regulating the expression of kitlga. However, two cAMP-activated effectors, protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac), had converse effects. PKA promoted whereas Epac inhibited the expression of kitlga, as demonstrated by the respective activators. Interestingly, cAMP also appeared to exert differential effects on kitlga expression at different stages of follicle development during folliculogenesis, significantly stimulating kitlga expression at the early growth stage but suppressing it at the full-grown stage before final oocyte maturation, implying a potential mechanism for differential effects of the same pathway at different stages. The inhibitory effect of forskolin (activator of adenylate cyclase) and H89 (inhibitor of PKA) on IGF-I-induced expression of kitlga suggested cross-talk between the cAMP and IGF-I-activated PI3K-Akt pathways. This study, together with our previous findings on IGF-I regulation of kitlga expression, provides important clues to the underlying mechanism that regulates Kit ligand expression during folliculogenesis in the ovary.
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PMID:Differential regulation of kit ligand A (kitlga) expression in the zebrafish ovarian follicle cells--evidence for the existence of a cyclic adenosine 3', 5' monophosphate-mediated binary regulatory system during folliculogenesis. 2554 47


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