Subcellular localization and regulation of type-1C and type-5 phosphodiesterases

Dolci, Susanna; Belmonte, Alessia; Santone, Rocco; Giorgi, Mauro; Pellegrini, Manuela; Carosa, Eleonora; Piccione, Emilio; Lenzi, Andrea; Jannini, Emmanuele A.

doi:10.1016/j.bbrc.2006.01.035

Cited by 48 publications

(43 citation statements)

References 42 publications

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“…Strikingly, we found that only T98G cells expressed high levels of PDE5, along with PDE1C, but not PDE1A and PDE3A, that represent other phosphodiesterases specific for cGMP hydrolysis (Supplementary Figure 1A-1D), while PDE6 and PDE11 were not expressed (not shown). PDE5 localized diffusely throughout the cell, but it was particularly concentrated in centrosomes [27] (Supplementary Figure 1B). We found that all the glioblastoma cell lines but A172 cell line expressed GUCY1A2, GUCY1A3, GUCY1B3, the subunits of the the dimeric soluble GC receptor activated by NO, as well as NPR2, the receptor-coupled GC isoform that binds C-type natriuretic peptide (CNP) (Supplementary Figure 1E).…”

Section: Resultsmentioning

confidence: 99%

Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome

et al. 2017

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Expression of type 5 phosphodiesterase (PDE5), a cGMP-specific hydrolytic enzyme, is frequently altered in human cancer, but its specific role in tumorigenesis remains controversial. Herein, by analyzing a cohort of 69 patients affected by glioblastoma multiforme (GBM) who underwent chemo- and radiotherapy after surgical resection of the tumor, we found that PDE5 was strongly expressed in cancer cells in about 50% of the patients. Retrospective analysis indicated that high PDE5 expression in GBM cells significantly correlated with longer overall survival of patients. Furthermore, silencing of endogenous PDE5 by short hairpin lentiviral transduction (sh-PDE5) in the T98G GBM cell line induced activation of an invasive phenotype. Similarly, pharmacological inhibition of PDE5 activity strongly enhanced cell motility and invasiveness in T98G cells. This invasive phenotype was accompanied by increased secretion of metallo-proteinase 2 (MMP-2) and activation of protein kinase G (PKG). Moreover, PDE5 silencing markedly enhanced DNA damage repair and cell survival following irradiation. The enhanced radio-resistance of sh-PDE5 GBM cells was mediated by an increase of poly(ADP-ribosyl)ation (PARylation) of cellular proteins and could be counteracted by poly(ADP-ribose) polymerase (PARP) inhibitors. Conversely, PDE5 overexpression in PDE5-negative U87G cells significantly reduced MMP-2 secretion, inhibited their invasive potential and interfered with DNA damage repair and cell survival following irradiation. These studies identify PDE5 as a favorable prognostic marker for GBM, which negatively affects cell invasiveness and survival to ionizing radiation. Moreover, our work highlights the therapeutic potential of targeting PKG and/or PARP activity in this currently incurable subset of brain cancers.

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Section: Resultsmentioning

confidence: 99%

Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome

et al. 2017

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“…Regarding cGMP, we could think that PDE1 and PDE5 may have a common pattern of regulation in cardiomyocytes. Indeed, they share some common intracellular localization like the Z-bands [36], [58], [69] and participate to contractile events [70], [71]. They are implicated also in cell growth and survival with nuclear localizations for PDE1A [71] and PDE1C [69] and centrosomal localization for PDE5A [69].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, they share some common intracellular localization like the Z-bands [36], [58], [69] and participate to contractile events [70], [71]. They are implicated also in cell growth and survival with nuclear localizations for PDE1A [71] and PDE1C [69] and centrosomal localization for PDE5A [69]. Their activities were simultaneously increased in vascular smooth muscle cell proliferation [60], [70] and herein in cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

Concerted Regulation of cGMP and cAMP Phosphodiesterases in Early Cardiac Hypertrophy Induced by Angiotensin II

et al. 2010

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Left ventricular hypertrophy leads to heart failure and represents a high risk leading to premature death. Cyclic nucleotides (cAMP and cGMP) play a major role in heart contractility and cyclic nucleotide phosphodiesterases (PDEs) are involved in different stages of advanced cardiac diseases. We have investigated their contributions in the very initial stages of left ventricular hypertrophy development. Wistar male rats were treated over two weeks by chronic infusion of angiotensin II using osmotic mini-pumps. Left cardiac ventricles were used as total homogenates for analysis. PDE1 to PDE5 specific activities and protein and mRNA expressions were explored.Rats developed arterial hypertension associated with a slight cardiac hypertrophy (+24%). cAMP-PDE4 activity was specifically increased while cGMP-PDE activities were broadly increased (+130% for PDE1; +76% for PDE2; +113% for PDE5) and associated with increased expressions for PDE1A, PDE1C and PDE5A. The cGMP-PDE1 activation by Ca2+/CaM was reduced. BNP expression was increased by 3.5-fold, while NOX2 expression was reduced by 66% and AMP kinase activation was increased by 64%. In early cardiac hypertrophy induced by angiotensin II, all specific PDE activities in left cardiac ventricles were increased, favoring an increase in cGMP hydrolysis by PDE1, PDE2 and PDE5. Increased cAMP hydrolysis was related to PDE4. We observed the establishment of two cardioprotective mechanisms and we suggest that these mechanisms could lead to increase intracellular cGMP: i) increased expression of BNP could increase “particulate” cGMP pool; ii) increased activation of AMPK, subsequent to increase in PDE4 activity and 5′AMP generation, could elevate “soluble” cGMP pool by enhancing NO bioavailability through NOX2 down-regulation. More studies are needed to support these assumptions. Nevertheless, our results suggest a potential link between PDE4 and AMPK/NOX2 and they point out that cGMP-PDEs, especially PDE1 and PDE2, may be interesting therapeutic targets in preventing cardiac hypertrophy.

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“…Although much less extensively studied, growing evidence also supports an important role for compartmentation of cGMP-based cellular signaling. Indeed, putative PKG-binding proteins (GKAPs) have been identified in certain cells (17,18) and selective subcellular distribution of cGMP-activated kinases (PKG) and cGMP-hydrolyzing PDEs has also been reported (19)(20)(21). For example, a model in which distinct PDEs selectively regulate either plasma membrane, or cytosolic, cGMP ''pools,'' has emerged from recent experiments using heterologously expressed cGMP biosensors (19,21).…”

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confidence: 99%

Compartmentation and compartment-specific regulation of PDE5 by protein kinase G allows selective cGMP-mediated regulation of platelet functions

Wilson

Elbatarny²,

Crawley³

et al. 2008

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

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It is generally accepted that nitric oxide (NO) donors, such as sodium nitroprusside (SNP), or phosphodiesterase 5 (PDE5) inhibitors, including sildenafil, each impact human platelet function. Although a strong correlation exists between the actions of NO donors in platelets and their impact on cGMP, agents such as sildenafil act without increasing global intra-platelet cGMP levels. This study was undertaken to identify how PDE5 inhibitors might act without increasing cGMP. Our data identify PDE5 as an integral component of a protein kinase G1␤ (PKG1␤)-containing signaling complex, reported previously to coordinate cGMP-mediated inhibition of inositol-1, 4, 5-trisphosphate receptor type 1 (IP 3R1)-mediated Ca 2؉ -release. PKG1␤ and PDE5 did not interact in subcellular fractions devoid of IP 3R1 and were not recruited to IP3R1-enriched membranes in response to cGMP-elevating agents. Activation of platelet PKG promoted phosphorylation and activation of the PDE5 fraction tethered to the IP 3R1-PKG complex, an effect not observed for the nontethered PDE5. Based on these findings, we elaborate a model in which PKG selectively activates PDE5 within a defined microdomain in platelets and propose that this mechanism allows spatial and temporal regulation of cGMP signaling in these cells. Recent reports indicate that sildenafil might prove useful in limiting in-stent thrombosis and the thrombotic events associated with the acute coronary syndromes (ACS), situations poorly regulated with currently available therapeutics. We submit that our findings may define a molecular mechanism by which PDE5 inhibition can differentially impact selected cellular functions of platelets, and perhaps of other cell types.calcium ͉ PKG

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Subcellular localization and regulation of type-1C and type-5 phosphodiesterases

Cited by 48 publications

References 42 publications

Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome

Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome

Concerted Regulation of cGMP and cAMP Phosphodiesterases in Early Cardiac Hypertrophy Induced by Angiotensin II

Compartmentation and compartment-specific regulation of PDE5 by protein kinase G allows selective cGMP-mediated regulation of platelet functions

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