Role of Cyclic Nucleotides in Growth Control

Pastan, Ira; Johnson, George S.; Anderson, Wayne B.

doi:10.1146/annurev.bi.44.070175.002423

Cited by 672 publications

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“…However, none of these hypotheses have so far gained definitive support. The present study of the effects of DTIC on phosphodiesterase and cAMP in liver was provoked by the growthinhibitory and differentiating effect of cAMP on many cell types (Pastan et al, 1975;Friedman, 1976), and by the fact that several other imidazole and imidazolidinone derivatives have been shown to be cAMP phosphodiesterase inhibitors (Chasin & Harris, 1976). DTIC inhibits cells in G1 as well as G2 (Bono, 1976;Gerulath et al, 1974), which could be compatible with a cAMP-mediated effect (Friedman et al, 1976).…”

Section: Discussionmentioning

confidence: 99%

“…Although the role of this nucleotide in the physiological growth regulation is still unclear and probably diverse, it has been firmly established that in several cultured cell lines proliferation is inhibited if the intracellular level of cAMP is artificially raised (Pastan et al, 1975;Friedman, 1976). It is conceivable, therefore, that drugs altering cAMP levels might contribute to pharmacological control of cancer-cell proliferation.…”

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confidence: 99%

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The antitumour agent 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide (DTIC) inhibits rat liver cAMP phosphodiesterase and amplifies hormone effects in hepatocytes and hepatoma cells

Larsson¹,

Haffner²,

Brłnstad³

et al. 1979

Br J Cancer

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Summary.-The antitumour agent 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC) was found to inhibit competitively the low-Km cyclic AMP phosphodiesterase activity in an ammonium-sulphate-precipitable fraction of the 2,000g supernatant of rat liver. With substrate concentration at 0-25 [M, 150 was 790 /tM for DTIC and 350 tM for theophylline. DTIC at 2 mm more than doubled the cAMP response to glucagon in hepatocytes and to adrenaline in MH1Cj hepatoma cells, indicating that it also exerts its inhibitory effect on the phosphodiesterase in intact cells. The possible contribution of the phosphodiesterase inhibition to the growthinhibitory and cytotoxic effects of DTIC is discussed.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The antitumour agent 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide (DTIC) inhibits rat liver cAMP phosphodiesterase and amplifies hormone effects in hepatocytes and hepatoma cells

Larsson¹,

Haffner²,

Brłnstad³

et al. 1979

Br J Cancer

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“…Conversely, the p85D aspartic mutant amplified cAMP stimulation of PI3K activity. Phosphorylation of Ser 83 by cAMP-PKA in p85a PI3K was also necessary for estrogen signaling as expression of p85A or p85D mutants inhibited or amplified, respecIntroduction Cyclic adenosine 3 0 5 0 monophosphate (cAMP) regulates the growth of many cells types (Pastan et al, 1975). Although cAMP can promote the growth of some cells, such as Swiss 3T3 fibroblasts and thyrocytes (Lee et al, 1998;Ariga et al, 2000), it inhibits proliferation in most cells (Magnaldo et al, 1989).…”

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confidence: 99%

p85 regulatory subunit of PI3K mediates cAMP–PKA and estrogens biological effects on growth and survival

et al. 2006

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Cyclic adenosine 3 0 5 0 monophosphate (cAMP) and protein kinase A (PKA) cooperate with phosphatidylinositol 3 0 kinase (PI3K) signals in the control of growth and survival. To determine the molecular mechanism(s) involved, we identified and mutagenized a specific serine (residue 83) in p85a PI3K , which is phosphorylated in vivo and in vitro by PKA. Expression of p85a PI3K mutants (alanine or aspartic substitutions) significantly altered the biological responses of the cells to cAMP. cAMP protection from anoikis was reduced in cells expressing the alanine version p85a PI3K . These cells did not arrest in G1 in the presence of cAMP, whereas cells expressing the aspartic mutant p85D accumulated in G1 even in the absence of cAMP. S phase was still efficiently inhibited by cAMP in cells expressing both mutants. The binding of PI3K to Ras p21 was greatly reduced in cells expressing p85A in the presence or absence of cAMP. Conversely, expression of the aspartic mutant stimulated robustly the binding of PI3K to p21 Ras in the presence of cAMP. Mutation in the Ser 83 inhibited cAMP, but not PDGF stimulation of PI3K. Conversely, the p85D aspartic mutant amplified cAMP stimulation of PI3K activity. Phosphorylation of Ser 83 by cAMP-PKA in p85a PI3K was also necessary for estrogen signaling as expression of p85A or p85D mutants inhibited or amplified, respectively, the binding of estrogen receptor to p85a and AKT phosphorylation induced by estrogens. The data presented indicate that: (1) phosphorylation of Ser 83 in p85a PI3K is critical for cAMP-PKA induced G1 arrest and survival in mouse 3T3 fibroblasts; (2) this site is necessary for amplification of estrogen signals by cAMP-PKA and related receptors. Finally, these data suggest a general mechanism of PI3K regulation by cAMP, operating in various cell types and under different conditions.

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“…EXPERIMENTAL EVIDENCE suggests that cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) play opposite roles in the control of cell growth and differentiation (Goldberg et al, 1975;Pastan et al, 1975;Watson, 1975;Friedman, 1976). In vitro, exogenous cGMP stimulates the proliferation of fibroblasts and lymphoid cells Whitfield et al, 1971;Diamantstein & Ulmer, 1975;Watson, 1975) whereas cAMP, or agents which increase its intracellular concentration, inhibit cell growth (Ryan & Heidrick, 1968;Yang & Vas, 1971;Pardee, 1974) and induce in malignant cells a normalappearing morphological or biochemical differentiation (Hsie & Puck, 1971;Johnson et al, 1971;Prasad et al, 1975).…”

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confidence: 99%

Patterns of cyclic nucleotides in normal and leukaemic human leucocytes

Peracchi¹,

Maiolo²,

Lombardi³

et al. 1980

Br J Cancer

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Summary.-Because recent observations indicate that metabolism of cyclic nucleotides may be altered in neoplastic cells, the intracellular levels of cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) were measured in mononuclear leukaemic and normal human leucocytes. The activities of adenylate cyclase, guanylate cyclase and cyclic nucleotide phosphodiesterases were also determined. Under basal conditions, cAMP levels were always higher in the normal leucocytes, whilst cGMP levels were of the same order of magnitude in both normal and leukaemic cells, causing the cAMP/cGMP ratios to be significantly lower in leukaemic leucocytes. Leukaemic cells significantly increased cyclic nucleotide levels in response to theophylline, but did not respond to serotonin, carbamylcholine or D,L-isoproterenol. Preincubation of these leucocytes with theophylline produced a detectable cAMP response to D,L-isoproterenol but no cGMP response to serotonin or carbamylcholine was found. Adenylate cyclase and guanylate cyclase were significantly lower in leukaemic than in normal cells, which could largely explain the abnormal cyclic nucleotide pattern found in human leukaemic leucocytes. In our experiments, cAMP phosphodiesterase activity was comparable in normal and leukaemic cells, whereas cGMP phosphodiesterase activity was undetectable in all mononuclear-leucocyte preparations with the methods used.

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Role of Cyclic Nucleotides in Growth Control

Cited by 672 publications

References 0 publications

The antitumour agent 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide (DTIC) inhibits rat liver cAMP phosphodiesterase and amplifies hormone effects in hepatocytes and hepatoma cells

The antitumour agent 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide (DTIC) inhibits rat liver cAMP phosphodiesterase and amplifies hormone effects in hepatocytes and hepatoma cells

p85 regulatory subunit of PI3K mediates cAMP–PKA and estrogens biological effects on growth and survival

Patterns of cyclic nucleotides in normal and leukaemic human leucocytes

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