The cAMP phosphodiesterase-4D7 (PDE4D7) is downregulated in androgen-independent prostate cancer cells and mediates proliferation by compartmentalising cAMP at the plasma membrane of VCaP prostate cancer cells

Henderson, D.; Byrne, Ashleigh M.; Dulla, Kalyan; Jenster, Guido; Hoffmann, Ralf; Baillie, George S.; Houslay, Miles D.

doi:10.1038/bjc.2014.22

Cited by 41 publications

(72 citation statements)

References 48 publications

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“…Thus, the diminished PDE10A activity at the plasma membrane associated with the motor disorder, reinforces the paradigm of compartmentalized cAMP dynamics being crucial for normal cell function (52). This has been exemplified before with the displacement of PDE4D7 from the plasma membrane, leading to aberrant cAMP signaling and an increase in the proliferation of prostate cancer cells (53). The shift of PDE10A2 GAF-A mutants to the cytosol also increases the turnover rate compared to the membrane-bound form.…”

Section: Discussionsupporting

confidence: 56%

“…FRET Imaging. FRET imaging experiments were performed 24 to 48 h after transfection of HEK293 cells as previously described (53), with the cytosolic EPAC-1 cAMP sensor (28) or a modified version encoding the FYXD1 subunit of Na 2+ /K + ATPase in the N-terminal region to direct the probe to the plasma membrane. For additional details, see SI Appendix, Supplementary Methods.…”

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confidence: 99%

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Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme

Tejeda

Whiteley

Deeb

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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A robust body of evidence supports the concept that phosphodiesterase 10A (PDE10A) activity in the basal ganglia orchestrates the control of coordinated movement in human subjects. Although human mutations in the PDE10A gene manifest in hyperkinetic movement disorders that phenocopy many features of early Huntington’s disease, characterization of the maladapted molecular mechanisms and aberrant signaling processes that underpin these conditions remains scarce. Recessive mutations in the GAF-A domain have been shown to impair PDE10A function due to the loss of striatal PDE10A protein levels, but here we show that this paucity is caused by irregular intracellular trafficking and increased PDE10A degradation in the cytosolic compartment. In contrast to GAF-A mutants, dominant mutations in the GAF-B domain of PDE10A induce PDE10A misfolding, a common pathological phenotype in many neurodegenerative diseases. These data demonstrate that the function of striatal PDE10A is compromised in disorders where disease-associated mutations trigger a reduction in the fidelity of PDE compartmentalization.

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Section: Discussionsupporting

confidence: 56%

mentioning

confidence: 99%

Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme

Tejeda

Whiteley

Deeb

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…However, in marked contrast to this, once PCa cells become androgen insensitive/independent (castration resistant), expression of PDE4D7 declines [15, 16]. …”

Section: Introductionmentioning

confidence: 99%

Human PDE4D isoform composition is deregulated in primary prostate cancer and indicative for disease progression and development of distant metastases

et al. 2016

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Phosphodiesterase 4D7 was recently shown to be specifically over-expressed in localized prostate cancer, raising the question as to which regulatory mechanisms are involved and whether other isoforms of this gene family (PDE4D) are affected under the same conditions.We investigated PDE4D isoform composition in prostatic tissues using a total of seven independent expression datasets and also included data on DNA methylation, copy number and AR and ERG binding in PDE4D promoters to gain insight into their effect on PDE4D transcription.We show that expression of PDE4D isoforms is consistently altered in primary human prostate cancer compared to benign tissue, with PDE4D7 being up-regulated while PDE4D5 and PDE4D9 are down-regulated. Disease progression is marked by an overall down-regulation of long PDE4D isoforms, while short isoforms (PDE4D1/2) appear to be relatively unaffected. While these alterations seem to be independent of copy number alterations in the PDE4D locus and driven by AR and ERG binding, we also observed increased DNA methylation in the promoter region of PDE4D5, indicating a long lasting alteration of the isoform composition in prostate cancer tissues.We propose two independent metrics that may serve as diagnostic and prognostic markers for prostate disease: (PDE4D7 - PDE4D5) provides an effective means for distinguishing PCa from normal adjacent prostate, whereas PDE4D1/2 - (PDE4D5 + PDE4D7 + PDE4D9) offers strong prognostic potential to detect aggressive forms of PCa and is associated with metastasis free survival. Overall, our findings highlight the relevance of PDE4D as prostate cancer biomarker and potential drug target.

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“…Recent findings from other groups support these observations. To date, three PDEs, PDE4 (Henderson, et al 2014; Kashiwagi, et al 2012; Sarwar, et al 2014), PDE5, and PDE11 (Chavez, et al 2013; Hamilton, et al 2013) have been associated with PCa.…”

Section: Discussionmentioning

confidence: 99%

Phosphodiesterase sequence variants may predispose to prostate cancer

Alexandre¹,

Horvath²,

Szarek³

et al. 2015

Endocrine-Related Cancer

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We hypothesized that mutations that inactivate phosphodiesterase (PDE) activity and lead to increased cyclic AMP (cAMP) and cyclic GMP (cGMP) levels may be associated with prostate cancer (PCa). We sequenced the entire PDE coding sequences in the DNA of 16 biopsy samples from PCa patients. Novel mutations were confirmed in the somatic or germline state by Sanger sequencing. Data were then compared to the 1000 Genome Project. PDE, CREB and pCREB protein expression was also studied in all samples, in both normal and abnormal tissue, by immunofluorescence. We identified 3 previously described PDE sequence variants that were significantly higher in PCa. Four novel sequence variations, one each in the PDE4B, PDE6C, PDE7B and PDE10A genes, respectively, were also found in the PCa samples. Interestingly, PDE10A and PDE4B novel variants that were present in 19% and 6% of the patients, respectively, were found in the tumor tissue only. In patients carrying PDE defects, there was pCREB accumulation (p<0.001), and an increase of the pCREB/CREB ratio (patients 0.97± 0.03; controls 0.52± 0.03; p-value < 0.001) by immunohistochemical analysis. We conclude that PDE sequence variants may play a role in the predisposition and/or progression to PCa at the germline and/or somatic state, respectively. Larger such studies are needed to confirm these findings.

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The cAMP phosphodiesterase-4D7 (PDE4D7) is downregulated in androgen-independent prostate cancer cells and mediates proliferation by compartmentalising cAMP at the plasma membrane of VCaP prostate cancer cells

Cited by 41 publications

References 48 publications

Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme

Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme

Human PDE4D isoform composition is deregulated in primary prostate cancer and indicative for disease progression and development of distant metastases

Phosphodiesterase sequence variants may predispose to prostate cancer

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