Cloning and characterization of PDE7B, a cAMP-specific phosphodiesterase

Hetman, Joanna; Soderling, Scott H.; Glavas, Natalie A.; Beavo, Joseph A.

doi:10.1073/pnas.97.1.472

Cited by 140 publications

(93 citation statements)

References 14 publications

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“…These data indicate that these PDEs do not contribute significant cAMP hydrolysis in DLBCL. In addition, in agreement with earlier work, 18,19 but contrary to a recent report in chronic lymphoid leukemia (CLL), 20 we found that PDE7B is not expressed in lymphoid cells (DLBCL) and that the PDE7-specific inhibitor BRL-50481 is largely ineffective in DLBCL cell lines (data not shown). These data suggested that the observed cAMP-mediated inhibition of SYK is directly controlled by PDE4B expression/activity.…”

Section: Camp Inhibits Syk Activity In Normal B Cellscontrasting

confidence: 56%

Rational combined targeting of phosphodiesterase 4B and SYK in DLBCL

Kim

Rai

McKeller

et al. 2009

Blood

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Identification of rational therapeutic targets is an important strategy to improve the cure rate of diffuse large B-cell lymphoma (DLBCL). We previously showed that inhibition of the phosphodiesterase 4B (PDE4B) unleashes cyclic-AMP (cAMP) inhibitory effects toward the PI3K/AKT pathway and induces apoptosis. These data raised important considerations as to which upstream regulators mediate cAMP inhibition of PI3K/AKT, and how identifying this signaling route could be translated into clinical initiatives. We found that in normal and malignant B cells, cAMP potently inhibit the phosphorylation and activity of the tyrosine kinase SYK. Using genetic models of gainand loss-of-function, we demonstrated the essential role for PDE4B in controlling these effects in DLBCL. Furthermore, we used a constitutively active SYK mutant to confirm its central role in transducing cAMP effects to PI3K/AKT. Importantly, given SYK credentials as a therapeutic target in B-cell tumors, we explored the role of PDE4B in these responses. In multiple DLBCL models, we found that genetically, hence specifically, inhibiting PDE4B expression significantly improved the efficacy of SYK inhibitors. Our data defined a hitherto unknown role for cAMP in negatively regulating SYK and indicate that combined inhibition of PDE4B and SYK should be actively pursued. (Blood. 2009;113: 6153-6160)

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Section: Camp Inhibits Syk Activity In Normal B Cellscontrasting

confidence: 56%

Rational combined targeting of phosphodiesterase 4B and SYK in DLBCL

Kim

Rai

McKeller

et al. 2009

Blood

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“…However, the description of different cAMP pools [30] for PDE4 and PDE7, and the fact that PDE7 acts on low concentrations of cAMP [14] may explain the differences observed in allergic models between the two isoenzymes.…”

Section: Discussionmentioning

confidence: 99%

“…Within the PDE7 family, two isoforms have been cloned in mice, rats and humans, namely PDE7A [12] and PDE7B [13,14], and similar patterns of tissue expression have been described in humans and mice [15]. The PDE7A sub-type is predominantly expressed and functional in lymphocytes [16,17].…”

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confidence: 99%

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Lack of involvement of type 7 phosphodiesterase in an experimental model of asthma

Chevalier¹,

Lagente²,

Dupont³

et al. 2011

European Respiratory Journal

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Type 7 phosphodiesterases (PDE7) are responsible for the decrease of intracellular cyclic AMP (cAMP) in many cells involved in allergic asthma by suppressing their potential to respond to many activating stimuli. The elevation of intracellular cAMP has been associated with immunosuppressive and anti-inflammatory activities and represents a potential treatment of asthma.Our aim was to evaluate the impact of the deletion of the murine phosphodiesterase (PDE)7B gene and then to evaluate the efficacy of a newly described selective PDE7A and -B inhibitor on an ovalbumin (OVA)-induced airway inflammation and airway hyperreactivity (AHR) model in mice.Inflammation was determined 72 h after single OVA challenge or 24 h after multiple challenges by the relative cell influx and cytokine content in bronchoalveolar lavage fluid. AHR and immunoglobulin E levels in serum were determined after multiple challenges.For the first time, we have demonstrated that the deletion of the PDE7B gene or the pharmacological inhibition of PDE7A and -B had no effect on all the parameters looked at in this model. These results highlight the absence of any implication of the PDE7 enzyme in our model.

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“…Details of this analysis are to be published. An important difference in the FMT gene list is that it included Pde7b, a high-affinity cAMP-specific phosphodiesterase anticipated to be upregulated in response to elevated PKA activity (Hetman et al, 2000), and Sphingosine kinase 1, which is functionally upregulated in response to PKA activation (Rius et al, 1997). …”

Section: Real Data Examplementioning

confidence: 99%

Fully Moderated T-statistic for Small Sample Size Gene Expression Arrays

Gulati²,

Fernández³

et al. 2011

Statistical Applications in Genetics and Molecular Biology

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Gene expression microarray experiments with few replications lead to great variability in estimates of gene variances. Several Bayesian methods have been developed to reduce this variability and to increase power. Thus far, moderated t methods assumed a constant coefficient of variation (CV) for the gene variances. We provide evidence against this assumption, and extend the method by allowing the CV to vary with gene expression. Our CV varying method, which we refer to as the fully moderated t-statistic, was compared to three other methods (ordinary t, and two moderated t predecessors). A simulation study and a familiar spike-in data set were used to assess the performance of the testing methods. The results showed that our CV varying method had higher power than the other three methods, identified a greater number of true positives in spike-in data, fit simulated data under varying assumptions very well, and in a real data set better identified higher expressing genes that were consistent with functional pathways associated with the experiments.

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Cloning and characterization of PDE7B, a cAMP-specific phosphodiesterase

Cited by 140 publications

References 14 publications

Rational combined targeting of phosphodiesterase 4B and SYK in DLBCL

Rational combined targeting of phosphodiesterase 4B and SYK in DLBCL

Lack of involvement of type 7 phosphodiesterase in an experimental model of asthma

Fully Moderated T-statistic for Small Sample Size Gene Expression Arrays

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