Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclic AMP can profoundly influence the growth and differentiation of neuronal cells in culture. In this study, the relationship between this second messenger signal transduction pathway, cell differentiation, and the expression of a retinoid-responsive, thymosin beta-10 gene was examined. Thymosin beta-10 and cognate mRNA were expressed at high levels in actively proliferating rat B104 neuroblastoma cells cultured in medium containing 10% FCS. These cells were induced to differentiate in the presence of the cAMP analog N6, 2'-O-dibutyryladenosine 3':5'-cyclic monophosphate (Bt2-cAMP) (1 mM) and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) (100 microM). Expression of thymosin beta-10 mRNA was markedly inhibited (greater than 90% and 70%, respectively) by these compounds. Addition of sodium butyrate (NaB, 1 mM) indicated that at least part of the inhibitory actions of Bt2-cAMP were due to esterase-induced release of butyrate from this compound. Adenosine (50 microM), a metabolic precursor to endogenous cyclic AMP, also inhibited accumulation of thymosin beta-10 mRNA (to less than 70% of control levels). The inhibitory action of Bt2-cAMP upon thymosin beta-10 mRNA levels was time dependent; levels were inhibited by greater than 50% 24 hours after addition of the cAMP analog and by greater than 90% after 72 hours. Serum starvation (0.2% FCS for seven days) provoked a marked increase in neurite out-growth; this morphological change was also accompanied by a modest inhibition of thymosin beta-10 mRNA accumulation. These findings together with previous observations imply that both cyclic AMP-dependent and retinoid-responsive mechanisms coordinate thymosin beta-10 gene expression during neuroembryogenesis.
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PMID:Influence of cyclic AMP and serum factors upon expression of a retinoid-responsive gene in neuroblastoma cells. 137 94

We have recently reported that prostaglandin D2 (PGD2) specifically elevates the intracellular cyclic AMP (cAMP) level in a fibroblastic cell line derived from bovine embryonic trachea (EBTr) (K. Sugama, T. Tanaka, H. Yokohama, M. Negishi, H. Hayashi, S. Ito, and O. Hayaishi, Biochim. Biophys. Acta, 1011: 75-80, 1989). Since the in vitro and in vivo inhibitory effects of PGD2 on cell growth are attributed to the dehydrate product 9-deoxy-delta 9,12-13,14-dihydro-PGD2 (delta 12-PGJ2), the role of cAMP as a mediator of PGD2-induced cell growth has been questioned. In this study we investigated the effects of PGD2 on cAMP level, DNA synthesis, and c-myc expression using EBTr cells growth-arrested by serum starvation. Quiescent EBTr cells synchronously resumed [3H]thymidine incorporation at 12 h after the addition of serum, an incorporation which ended at 21 h. PGD2 at 1 microM inhibited approximately 30% incorporation without any delay of initiation, and it also caused a rapid increase in the cAMP level at a maximum of 10 min. The inhibition of [3H]thymidine incorporation was increased 40-45% by 5 microM 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor. The expression of c-myc mRNA induced by serum at 1-4 h was also inhibited by PGD2. Time-course studies support the association between the reduction of c-myc expression and the successive inhibition of DNA synthesis by PGD2. The dose dependency of PGD2 for these three processes correlated well with each other, and the effects were evident at as low as 10 nM and specific for PGD2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclic AMP-mediated inhibition of cell growth by prostaglandin D2 in a fibroblastic cell line (EBTr). 170 11

Cyclic AMP phosphodiesterase was measured in liver homogenates and microdissected periportal and perivenous liver tissue from rats in different dietary states under different conditions of substrate saturation and effector stimulation. A radiochemical microtest, more sensitive by 2-3 orders of magnitude than the usual assay, was established for the determination of the activity in liver samples corresponding to 200-800 ng dry weight. At saturating cyclic AMP concentrations (46 microM) phosphodiesterase was homogeneously distributed within the liver acinus of fed rats. Starvation for 48 h led to a decrease in the overall activity and to a heterogenous distribution with slightly higher activities in the perivenous zone. At physiological cyclic AMP concentrations (1.8 microM) phosphodiesterase showed a flat zonal gradient in livers of fed rats with higher levels in the periportal zone; after 48 h starvation it was homogeneously distributed. In the presence of cyclic GMP (2 microM) the basal activity at physiological substrate concentrations was stimulated to a greater extent in the perivenous zone. This led to a homogeneous activity distribution in the fed state and to a heterogenous pattern with a slight perivenous maximum in the fasted state. Thus there was no or only a small zonal heterogeneity of signal transmitting enzymes such as cyclic AMP phosphodiesterase and glucagon-stimulated adenylate cyclase (Zierz and Jungermann 1984). This similar signal transducing capacity in the periportal and the perivenous area will contribute to maintain the zonation of signal input due to the hormone concentration gradients across the liver acinus.
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PMID:Distribution of cyclic AMP phosphodiesterase in microdissected periportal and perivenous rat liver tissue with different dietary states. 171 30

Disruption of the cyr1 gene of Schizosaccharomyces pombe, which encodes adenylyl cyclase, did not confer lethality to fission yeast cells, although they grew 40% slower than wild-type strains in complete medium. These cells contained no measurable amount of cAMP and no adenylyl cyclase activity. When h+ and h- cyr1 disruptants were mixed, they underwent mating even in rich medium. Propagation of homothallic cyr1 disruptants was difficult, probably because such cells readily mate and produce asci and thus stop growing. A greater than 10-fold increase in the amount of cyr1 mRNA was observed when cloned cyr1+ was introduced into Sch. pombe cells on a multicopy plasmid. The total adenylyl cyclase activity was similarly high in these transformants. However, the level of intracellular cAMP was hardly affected. Evidence suggests that this was not due to increased phosphodiesterase activity. Thus, cAMP level in growing fission yeast cells appears to be regulated not by the amount of adenylyl cyclase protein but by a feedback mechanism at the enzyme level. The cAMP level fell by approximately 50% under nitrogen starvation, which triggers sexual development in Sch. pombe. We suggest that fission yeast controls the level of intracellular cAMP primarily to regulate sexual development rather than to drive or arrest the cell cycle.
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PMID:Adenylyl cyclase is dispensable for vegetative cell growth in the fission yeast Schizosaccharomyces pombe. 217 64

Cholera toxin produced a dose-dependent decrease in the restimulation of G0/G1 traverse in density-arrested human fibroblasts but did not inhibit the stimulation of cells arrested in G0 after serum starvation at low density. In addition, cholera toxin did not inhibit the proliferation of sparse logarithmically growing human fibroblasts, even when low concentrations of the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) were also present. However, the final density to which sparse cells grew was limited by cholera toxin, when added either alone or together with low concentrations of IBMX. In contrast, high concentrations of the phosphodiesterase inhibitor alone produced a profound inhibition in the growth of sparse human fibroblasts. IBMX produced an inhibition both in the G1 and in the G2 phases of the cell cycle by a mechanism(s) that was not related to the magnitude of the increases in adenosine 3',5'-cyclic monophosphate concentrations.
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PMID:Effects of cholera toxin and isobutylmethylxanthine on growth of human fibroblasts. 242 59

One of the earliest events in the development of Dictyostelium discoideum is the induction of the cyclic nucleotide phosphodiesterase gene. During vegetative growth a small amount of secreted phosphodiesterase is synthesized. The phosphodiesterase transcript which is responsible for the vegetative enzyme has a size of 1800 nucleotides. Soon after starvation begins a more abundant mRNA with a size of 2200 nucleotides is synthesized by the developing cells. The induction of the 2200-nucleotide mRNA is dependent on protein synthesis and takes place under all regimens of growth and starvation. When growth is in axenic medium and development is in phosphate buffer, the appearance of the larger transcript is very rapid, occurring within 30 min after the onset of starvation. The initial burst of phosphodiesterase mRNA synthesis is followed by a decline in mRNA abundance unless the cells are stimulated by cAMP. When cells are grown on bacteria and development takes place on filter paper, the larger transcript appears after 4 hr, reaches a peak at 10-12 hr of development, and then slowly disappears. When prestalk and prespore cells from migrating slugs are separated, a small amount of transcript can be found only in the prestalk cells. A series of mutants blocked early in development make very little phosphodiesterase transcript or are otherwise abnormal in expression of the phosphodiesterase mRNA. Together these mutants define five independent genetic loci which affect the accumulation of the phosphodiesterase mRNA. These are the pdsA, fgdA, fgdC, fgdD, and fgdE genes.
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PMID:The expression of two transcripts of the phosphodiesterase gene during the development of Dictyostelium discoideum. 282 53

sra5 mutations in Saccharomyces cerevisiae were previously shown to suppress the inefficient growth of ras2 strains on nonfermentable carbon sources and to result in deficient low-Km cyclic AMP (cAMP) phosphodiesterase activity. We have cloned SRA5 by complementation. It maps to the right arm of chromosome XV, tightly linked to PRT1, and its sequence matches the sequence of PDE2, encoding the low-Km cAMP phosphodiesterase. Disruptions of SRA5 allowed ras1 ras2 strains to grow either on rich media supplemented with cAMP or on minimal media without exogenous cAMP. sra5 strains failed to survive prolonged nitrogen starvation in the presence of exogenous cAMP.
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PMID:SRA5 encodes the low-Km cyclic AMP phosphodiesterase of Saccharomyces cerevisiae. 282 10

A gene, PDE2, has been cloned from the yeast Saccharomyces cerevisiae that, when present in high copy, reverses the phenotypic effects of RAS2Val19, a mutant form of the RAS2 gene that renders yeast cells sensitive to heat shock and starvation. It has previously been shown that the RAS proteins are potent activators of yeast adenylate cyclase. We report here that PDE2 encodes a high-affinity cAMP phosphodiesterase that shares sequence homology with animal cell phosphodiesterases. These results therefore imply that the effects of RAS2Val19 are mediated through its changes in cAMP concentration.
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PMID:Cloning and characterization of the high-affinity cAMP phosphodiesterase of Saccharomyces cerevisiae. 302 32

Meiosis and sporulation of Saccharomyces cerevisiae are initiated in a guanine auxotroph by guanine deprivation (E. Bautz Freese, Z. Olempska-Beer, A. Hartig, and E. Freese, Dev. Biol. 102:438-451, 1984). We used this condition to examine a hypothesis (K. Matsumoto, I. Uno, and T. Ishikawa, Cell 32:417-423, 1983) that initiation of meiosis requires a low level of cAMP. We found that, after guanine deprivation, the intracellular concentration of cAMP transiently decreased not more than 20% and not at all if the cAMP phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) was added to the medium. Under these conditions, at least 76% of the cells sporulated in the absence of IBMX, and almost 100% sporulated in its presence. The sporulating cells continually excreted cAMP and utilized the gluconeogenic carbon source. The cells failed to sporulate efficiently and to form four-spored asci if simultaneously deprived of guanine and carbon. After guanine deprivation in glucose medium, sporulation remained suppressed and intracellular cAMP was unchanged. We conclude that, under conditions of guanine starvation, cAMP deficiency is not required for initiation of meiosis and sporulation, cAMP is produced in excess and excreted to the medium, the cells sporulate better if the cAMP concentration is increased by addition of IBMX, the cells require a gluconeogenic carbon source for complete and efficient sporulation, and suppression of sporulation by glucose is not mediated by cAMP.
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PMID:Initiation of meiosis and sporulation in Saccharomyces cerevisiae does not require a decrease in cyclic AMP. 303 47

1. The rise in clearing-factor lipase activity that occurs when epididymal fat bodies from starved rats are incubated in appropriate media in vitro is inhibited in the presence of 6-N-2'-O-dibutyryl-3',5'-(cyclic)-AMP (1mm). 2. Inhibition occurs at a concentration of glucose in the incubation medium of 1.3mg./ml. or less, but not at a glucose concentration of 2.4mg./ml., unless caffeine (1mm), an inhibitor of 3',5'-(cyclic)-nucleotide phosphodiesterase, is also present. Caffeine (5mm) alone inhibits the rise in clearing-factor lipase activity at a glucose concentration of 2.4mg./ml. of medium. 3. The concentration of free fatty acids in the epididymal fat bodies normally falls during incubations in vitro as the rise in clearing-factor lipase activity occurs. In the presence of 1mm-6-N-2'-O-dibutyryl-3',5'-(cyclic)-AMP, however, either the tissue free fatty acid concentration is increased or it does not fall to the same extent. The concentration of glucose in the incubation medium is important in determining the direction and extent of the changes in tissue free fatty acid concentration that occur in the presence of 6-N-2'-O-dibutyryl-3',5'-(cyclic)-AMP. 4. Free fatty acid concentrations in epididymal fat bodies in vivo rise as the clearing-factor lipase activity of the tissue falls during starvation. 5. The possibility that the concentration of 3',5'-(cyclic)-AMP in adipose tissue may regulate clearing-factor lipase activity, and that the regulation may occur through effects of the nucleotide on tissue free fatty acid concentrations, is discussed.
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PMID:Clearing-factor lipase in adipose tissue. A possible role of adenosine 3',5'-(cyclic)-monophosphate in the regulation of its activity. 430 48


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