Structure-activity relationships for activation of adenylate cyclase by the diterpene forskolin and its derivatives

Seamon, Kenneth B.; Daly, John W.; Metzger, H.; Souza, N. J. De; Reden, J.

doi:10.1021/jm00357a021

Cited by 144 publications

(82 citation statements)

References 4 publications

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“…Forskolin has been reported to have activities dissociable from its ability to elevate cAMP (19,45). These dissociable activities are also regulated by 1,9-dideoxyforskolin, a forskolin analog which is inactive in stimulating adenylate cyclase (39). To provide additional evidence that activation of adenylate cyclase is necessary for forskolininduced c-myc expression, the ability of forskolin and its analogs to increase intracellular cAMP was determined.…”

Section: Resultsmentioning

confidence: 99%

Platelet-derived growth factor-stimulated c-myc RNA accumulation in MG-63 human osteosarcoma cells is independent of both protein kinase A and protein kinase C.

Frick¹,

Scher²

1990

Mol. Cell. Biol.

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Treatment of quiescent MG-63 cells with 12-0-tetradecanoylphorbol-13-acetate (TPA) or platelet-derived growth factor (PDGF) stimulates the rapid accumulation of c-myc RNA. We have now determined that a similar effect can be induced by cAMP. Treatment with forskolin (an activator of adenylate cyclase), IBMX (a phosphodiesterase inhibitor), PGE1, and isoproterenol stimulated accumulation of both cAMP and c-myc RNA, but no increase in either cAMP or c-myc RNA was seen with the inactive forskolin analog 1,9-dideoxyforskolin. Forskolin and IBMX acted synergistically in stimulating accumulation of both cAMP and c-myc RNA. However, three lines of evidence indicated that PDGF action is not mediated by cAMP. First, PDGF treatment caused no elevation of cAMP within 1 h, even in the presence of IBMX. Second, the kinetics of c-myc RNA elevation after treatment with PDGF or forskolin were similar, ruling out delayed onset of cAMP stimulation. Finally, simultaneous treatment with forskolin and the calcium ionophore A23187 enhanced the elevation of c-myc RNA levels; no such effect was seen with PDGF. We had previously shown that PDGF action is not affected by prior treatment of MG-63 cells with TPA, a treatment which desensitizes the c-myc response to TPA. Similarly, TPA pretreatment had minimal effect on forskolin or IBMX-induced c-myc expression. These data suggest that cAMP, phorbol esters, and PDGF act independently to stimulate c-myc RNA expression in MG-63 cells. However, nuclear runoff experiments and RNA half-life measurements demonstrated that PDGF, phorbol ester, and cAMP all act to increase the transcription of the MYC gene.

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Section: Resultsmentioning

confidence: 99%

Platelet-derived growth factor-stimulated c-myc RNA accumulation in MG-63 human osteosarcoma cells is independent of both protein kinase A and protein kinase C.

Frick¹,

Scher²

1990

Mol. Cell. Biol.

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“…3j). These compounds lead to an increase in cellular cAMP levels by targeting different enzymes involved in cAMP production, which culminates in the activation of PKA, a negative regulator of the Hh pathway [36,38]. The synergistic effect that we observed suggests that both compounds are active in our system yet neither one alone is effective in inhibiting Hh signaling.…”

Section: E F Gmentioning

confidence: 83%

In vivo analysis of compound activity and mechanism of action using epistasis in Drosophila

2010

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The recent establishment of high-throughput methods for culturing Drosophila provided a unique ability to screen compound libraries against complex disease phenotypes in the context of whole animals. However, as compound studies in Drosophila have been limited so far, the degree of conservation of compound activity between Drosophila and vertebrates or the effectiveness of feeding as a compound delivery system is not well known. Our comprehensive in vivo analysis of 27 small molecules targeting seven signaling pathways in Drosophila revealed a high degree of conservation of compound activity between Drosophila and vertebrates. We also investigated the mechanism of action of AY9944, one of the Hh pathway antagonists that we identified in our compound feeding experiments. Our epistasis analysis of AY9944 provided novel insights into AY9944's mechanism of action and revealed a novel role for cholesterol transport in Hh signal transduction.

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“…Figure 5 demonstrates that only forskolin evoked a significant change in Na ϩ uptake. At the concentration used, forskolin readily increases cAMP, leading to rapid activation of PKA (30). NCC activity was not altered by short-term stimulation with aldosterone or short-term activation of PKG or PKC (PMA).…”

Section: Thiazide-sensitive Na ϩ Uptake In Hncc-mdck Cells Is Increasmentioning

confidence: 95%

Functional Expression of the Human Thiazide-Sensitive NaCl Cotransporter in Madin-Darby Canine Kidney Cells

Jong¹,

Willems²,

Heuvel³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. The thiazide-sensitive Na ϩ -Cl Ϫ cotransporter (NCC), which is expressed on the apical membrane of epithelial cells lining the distal convoluted tubule, is responsible for the reabsorption of 5% to 10% of filtered Na ϩ and Cl Ϫ . To date, functional studies on the structural and regulatory requirements for localized trafficking and ion-transporting activity of NCC have been hampered by lack of a suitable cell system expressing this cotransporter. Reported here is the functional expression of human NCC (hNCC) in a polarized mammalian cell of renal origin-that is, the high-resistance Madin-Darby canine kidney (MDCK) cell. Western blot testing revealed that the cells predominantly expressed the complex glycosylated (approximately 140 kD) form of hNCC. hNCC was present primarily in the apical part of the cell. The functionality of hNCC was demonstrated by the gain of thiazide-sensitive Na ϩ uptake and transepithelial transport activity. Na ϩ uptake was significantly increased after short-term (15 min) treatment with forskolin, whereas cyclic guanosine monophosphate, wortmannin, phorbol 12-myriatate 13-acetate, and staurosporine were without effect. This indicates that hNCC activity is regulated through cyclic adenosine monophosphate, rather than via cyclic guanosine monophosphate, phosphoinositide 3-kinases or protein kinase C. Aldosterone did not alter Na ϩ uptake in the short term (15 min) but significantly increased the transport activity in the long term (16 h). The latter effect of aldosterone was due to an effect on the cytomegalovirus promoter/enhancer driving the expression of hNCC. hNCC-MDCK cells are a good model for the study of the regulation of apical trafficking and ion-transporting activity of hNCC.

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Structure-activity relationships for activation of adenylate cyclase by the diterpene forskolin and its derivatives

Cited by 144 publications

References 4 publications

Platelet-derived growth factor-stimulated c-myc RNA accumulation in MG-63 human osteosarcoma cells is independent of both protein kinase A and protein kinase C.

Platelet-derived growth factor-stimulated c-myc RNA accumulation in MG-63 human osteosarcoma cells is independent of both protein kinase A and protein kinase C.

In vivo analysis of compound activity and mechanism of action using epistasis in Drosophila

Functional Expression of the Human Thiazide-Sensitive NaCl Cotransporter in Madin-Darby Canine Kidney Cells

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