scholarly journals Cyclic AMP responses are suppressed in mammalian cells expressing the yeast low Km cAMP-phosphodiesterase gene.

1990 ◽  
Vol 265 (10) ◽  
pp. 5840-5846
Author(s):  
M M Van Lookeren Campagne ◽  
E Wu ◽  
R D Fleischmann ◽  
M M Gottesman ◽  
K W Chason ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Mammalian Cells ◽  
Camp Phosphodiesterase

Cloning and characterization of the low-affinity cyclic AMP phosphodiesterase gene of Saccharomyces cerevisiae

1987 ◽  
Vol 7 (10) ◽  
pp. 3629-3636
Author(s):  
J Nikawa ◽  
P Sass ◽  
M Wigler
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cyclic Amp ◽  
Copy Number ◽  
Growth Arrest ◽  
Yeast Cells ◽  
Phosphodiesterase Activity ◽  
Camp Phosphodiesterase ◽  
High Affinity ◽  
Cyclic Amp Phosphodiesterase

Saccharomyces cerevisiae contains two genes which encode cyclic AMP (cAMP) phosphodiesterase. We previously isolated and characterized PDE2, which encodes a high-affinity cAMP phosphodiesterase. We have now isolated the PDE1 gene of S. cerevisiae, which encodes a low-affinity cAMP phosphodiesterase. These two genes represent highly divergent branches in the evolution of phosphodiesterases. High-copy-number plasmids containing either PDE1 or PDE2 can reverse the growth arrest defects of yeast cells carrying the RAS2(Val-19) mutation. PDE1 and PDE2 appear to account for the aggregate cAMP phosphodiesterase activity of S. cerevisiae. Disruption of both PDE genes results in a phenotype which resembles that induced by the RAS2(Val-19) mutation. pde1- pde2- ras1- ras2- cells are viable.

scholarly journals Cyclic AMP compartmentation due to increased cAMP‐phosphodiesterase activity in transgenic mice with a cardiac‐directed expression of the human adenylyl cyclase type 8 (AC8)

2003 ◽  
Vol 17 (11) ◽  
pp. 1380-1391 ◽  
Author(s):  
Marie Georget ◽  
Philippe Mateo ◽  
Grégoire Vandecasteele ◽  
Larissa Lipskaia ◽  
Nicole Defer ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Transgenic Mice ◽  
Adenylyl Cyclase ◽  
Phosphodiesterase Activity ◽  
Camp Phosphodiesterase

Cyclic AMP-dependent protein kinase regulates sensitivity of cells to multiple drugs

1987 ◽  
Vol 7 (9) ◽  
pp. 3098-3106
Author(s):  
I Abraham ◽  
R J Hunter ◽  
K E Sampson ◽  
S Smith ◽  
M M Gottesman ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Mammalian Cells ◽  
Multiple Drug Resistance ◽  
Regulatory Subunit ◽  
Parent Cell ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
Antimitotic Drug ◽  
Multiple Drugs

The isolation of mutant cell lines affecting the activity of cyclic AMP (cAMP)-dependent protein kinase (PK-A) has made it possible to determine the function of this kinase in mammalian cells. We found that both a CHO cell mutant with a defective regulatory subunit (RI) for PK-A and a transfectant cell line expressing the same mutant kinase were sensitive to multiple drugs, including puromycin, adriamycin, actinomycin D, and some antimitotic drugs. The mutant and transfectant cells, after treatment with a concentration of the antimitotic drug colcemid that had no marked effect on the wild-type parent cell, had a severely disrupted microtubule network. The phenotype of hypersensitivity to the antimitotic drug colcemid was used to select revertants of the transfectant and the original mutant. These revertants simultaneously regained normal multiple drug resistance and cAMP sensitivity, thus establishing that the characteristics of colcemid sensitivity and cAMP resistance are linked. Four revertants of the transfectant reverted because of loss or rearrangement of the transfected mutant RI gene. These revertants, as well as one revertant selected from the original mutant, had PK-A activities equal to or higher than that of the parent. In these genetic studies, in which linkage of expression of a PK-A mutation with drug sensitivity is demonstrated, it was established that the PK-A system is involved in regulating resistance of mammalian cells to multiple drugs.

scholarly journals Cyclic AMP-dependent protein kinase regulates sensitivity of cells to multiple drugs.

1987 ◽  
Vol 7 (9) ◽  
pp. 3098-3106 ◽  
Author(s):  
I Abraham ◽  
R J Hunter ◽  
K E Sampson ◽  
S Smith ◽  
M M Gottesman ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Mammalian Cells ◽  
Multiple Drug Resistance ◽  
Regulatory Subunit ◽  
Parent Cell ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
Antimitotic Drug ◽  
Multiple Drugs

The isolation of mutant cell lines affecting the activity of cyclic AMP (cAMP)-dependent protein kinase (PK-A) has made it possible to determine the function of this kinase in mammalian cells. We found that both a CHO cell mutant with a defective regulatory subunit (RI) for PK-A and a transfectant cell line expressing the same mutant kinase were sensitive to multiple drugs, including puromycin, adriamycin, actinomycin D, and some antimitotic drugs. The mutant and transfectant cells, after treatment with a concentration of the antimitotic drug colcemid that had no marked effect on the wild-type parent cell, had a severely disrupted microtubule network. The phenotype of hypersensitivity to the antimitotic drug colcemid was used to select revertants of the transfectant and the original mutant. These revertants simultaneously regained normal multiple drug resistance and cAMP sensitivity, thus establishing that the characteristics of colcemid sensitivity and cAMP resistance are linked. Four revertants of the transfectant reverted because of loss or rearrangement of the transfected mutant RI gene. These revertants, as well as one revertant selected from the original mutant, had PK-A activities equal to or higher than that of the parent. In these genetic studies, in which linkage of expression of a PK-A mutation with drug sensitivity is demonstrated, it was established that the PK-A system is involved in regulating resistance of mammalian cells to multiple drugs.

scholarly journals Unique Significance of Dihomo-γ-Linolenic Acid Mechanisms for the Prevention of Thrombosis

1977 ◽  
Author(s):  
A. L. Willis
Keyword(s):  
Arachidonic Acid ◽  
Cyclic Amp ◽  
Linolenic Acid ◽  
Mode Of Action ◽  
Selective Inhibitor ◽  
O2 Uptake ◽  
Camp Phosphodiesterase ◽  
Platelet Production ◽  
Prevention Of Thrombosis ◽  
Stable Material

Common anti-platelet aggregatory agents act like aspirin to block cyclo-oxygenation of arachidonic acid (AA) to the endoperoxide PGH2. Alternatively, they act like PGE1 to increase platelet cyclic AMP (cAMP). Inhibition of platelet production of thromboxane (TX)A2 may also be desirable. Dihomo-γ-linolenic acid (DHLA) apparently acts through these and other mechanisms. Competition of DHLA with AA for vesicular gland cyclo-oxygenase occurred so that antiaggregatory PGE1 and PGH1 were produced at the expense of PGH2 and PGE2 (which together produce aggregation); O2 uptake was unimpaired. Consistent with such an action in platelets, the antiaggregatory effects of DHLA were prevented by aspirin or other inhibitors of cyclo-oxygenase and were enhanced by Ro 21–1724, a selective inhibitor of cAMP phosphodiesterase. Prior incubation of platelet microsomes with DHLA suppressed conversion of AA to a TXA2-like vasoconstrictor substance and to more stable material behaving like TXB2 on radio-TLC. In addition, DHLA may compete with dietary AA for incorporation into PG precursor pools. The multiple mode of action reported here supports a concept that DHLA is a natural anti-thrombotic factor of key importance.

scholarly journals Small-molecule allosteric activators of PDE4 long form cyclic AMP phosphodiesterases

2019 ◽  
Vol 116 (27) ◽  
pp. 13320-13329 ◽  
Author(s):  
Faisa Omar ◽  
Jane E. Findlay ◽  
Gemma Carfray ◽  
Robert W. Allcock ◽  
Zhong Jiang ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Small Molecule ◽  
Protein Complexes ◽  
Cyst Formation ◽  
Camp Signaling ◽  
Intracellular Camp ◽  
Camp Phosphodiesterase ◽  
Cellular Processes ◽  
Small Molecule Compound ◽  
Autosomal Dominant Polycystic Kidney

Cyclic AMP (cAMP) phosphodiesterase-4 (PDE4) enzymes degrade cAMP and underpin the compartmentalization of cAMP signaling through their targeting to particular protein complexes and intracellular locales. We describe the discovery and characterization of a small-molecule compound that allosterically activates PDE4 long isoforms. This PDE4-specific activator displays reversible, noncompetitive kinetics of activation (increased Vmax with unchanged Km), phenocopies the ability of protein kinase A (PKA) to activate PDE4 long isoforms endogenously, and requires a dimeric enzyme assembly, as adopted by long, but not by short (monomeric), PDE4 isoforms. Abnormally elevated levels of cAMP provide a critical driver of the underpinning molecular pathology of autosomal dominant polycystic kidney disease (ADPKD) by promoting cyst formation that, ultimately, culminates in renal failure. Using both animal and human cell models of ADPKD, including ADPKD patient-derived primary cell cultures, we demonstrate that treatment with the prototypical PDE4 activator compound lowers intracellular cAMP levels, restrains cAMP-mediated signaling events, and profoundly inhibits cyst formation. PDE4 activator compounds thus have potential as therapeutics for treating disease driven by elevated cAMP signaling as well as providing a tool for evaluating the action of long PDE4 isoforms in regulating cAMP-mediated cellular processes.

scholarly journals Cyclic AMP Controls mTOR through Regulation of the Dynamic Interaction between Rheb and Phosphodiesterase 4D

2010 ◽  
Vol 30 (22) ◽  
pp. 5406-5420 ◽  
Author(s):  
Hyun Wook Kim ◽  
Sang Hoon Ha ◽  
Mi Nam Lee ◽  
Elaine Huston ◽  
Do-Hyung Kim ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Mammalian Target Of Rapamycin ◽  
Dynamic Interaction ◽  
Negative Regulator ◽  
Camp Phosphodiesterase ◽  
Extracellular Stimuli ◽  
Phosphodiesterase 4D ◽  
Signaling Components ◽  
Camp Levels ◽  
Regulatory Event

ABSTRACT The mammalian target of rapamycin complex 1 (mTORC1) is a molecular hub that regulates protein synthesis in response to a number of extracellular stimuli. Cyclic AMP (cAMP) is considered to be an important second messenger that controls mTOR; however, the signaling components of this pathway have not yet been elucidated. Here, we identify cAMP phosphodiesterase 4D (PDE4D) as a binding partner of Rheb that acts as a cAMP-specific negative regulator of mTORC1. Under basal conditions, PDE4D binds Rheb in a noncatalytic manner that does not require its cAMP-hydrolyzing activity and thereby inhibits the ability of Rheb to activate mTORC1. However, elevated cAMP levels disrupt the interaction of PDE4D with Rheb and increase the interaction between Rheb and mTOR. This enhanced Rheb-mTOR interaction induces the activation of mTORC1 and cap-dependent translation, a cellular function of mTORC1. Taken together, our results suggest a novel regulatory mechanism for mTORC1 in which the cAMP-determined dynamic interaction between Rheb and PDE4D provides a key, unique regulatory event. We also propose a new role for PDE4 as a molecular transducer for cAMP signaling.

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