Disease relevance of PDE7A

• As treatment with the methylxanthine theophylline, a nonspecific PDE inhibitor, induces apoptosis in leukemic cells from patients with the B-lineage malignancy chronic lymphocytic leukemia (CLL), we sought to determine if PDE7A was a target of theophylline therapy in such cells [1].
• Refolding and purification of recombinant human PDE7A expressed in Escherichia coli as inclusion bodies [2].
• The development of dual-specificity compounds that inhibit PDE4 and PDE1, PDE3, PDE5 or PDE7 could be beneficial for the treatment of chronic inflammatory lung diseases and are currently being investigated [3].
• Intestinal Hcp1 mRNA content was not significantly changed by iron overload (600 mg/kg); however, it was increased to 170 % of controls 72 h after withdrawal of 0.7 ml of blood; the same treatment increased intestinal Cybrd1 mRNA to 900 % of controls [4].

High impact information on PDE7A

• Increased PDE7 in T cells correlated with decreased cAMP, increased interleukin-2 expression, and increased proliferation [5].
• Induction of adenosine 3',5'-monophosphate (cAMP)-specific phosphodiesterase-7 (PDE7) was found to be a consequence of such costimulation [5].
• Histone H3 phosphorylation and HCP-1 staining, which marks kinetochores, were reduced in the absence of either BIR-1 or AIR-2 [6].
• The localization of HCP-4 to the centromere is dependent on the centromeric histone HCP-3; in addition, HCP-3 and HCP-4 are both required for localization of a CENP-F-like protein, HCP-1, indicating an ordered assembly pathway [7].
• PDE7A and PDE7B exhibit the same general pattern of inhibitor specificity among the several drugs tested [8].

Biological context of PDE7A

• The activity of PDE7A isolated from the WSU-CLL cell line by immunoprecipitation was inhibited by theophylline and IBMX with IC50 values of 343.5 and 8.6 microM, respectively [1].
• IC242-mediated up-regulation of PDE7A was blocked by the protein kinase A (PKA) inhibitor H-89 [1].
• Alternative splicing of the high affinity cAMP-specific phosphodiesterase (PDE7A) mRNA in human skeletal muscle and heart [9].
• The DNA sequence of this skeletal muscle cDNA indicates that PDE7A2 is a novel 5' splice variant of PDE7A encoding an isoform with a novel, hydrophobic N terminus [9].
• Assignment of the mouse Pde7A gene to the proximal region of chromosome 3 and of the human PDE7A gene to chromosome 8q13 [10].

Anatomical context of PDE7A

• PDE7A is a recently described 3',5'-cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase (PDE) whose expression has been detected in T-cells [1].
• PDE7A is expressed in human B-lymphocytes and is up-regulated by elevation of intracellular cAMP [1].
• Immunoconfocal analyses showed that PDE7A was expressed in neutrophils and alveolar macrophages [11].
• Western analysis revealed expression of PDE7A in normal human splenic B-cells, primary CLL cells, and in a CLL-derived cell line (WSU-CLL) [1].
• The even distribution of PDE7A mRNA among fetal tissues and the relative abundance of its two mRNAs strongly suggest that the expression of PDE7A is regulated throughout development [9].

Associations of PDE7A with chemical compounds

• A potent selective inhibitor of PDE4 (IC50 = 0.00031 microM), RP 73401, which did not effectively suppress PDE7A (IC50 > 10 microM), inhibited the Df- and anti-CD3 MoAb-stimulated responses only weakly, even at 10 microM [12].
• HCP1 is a high affinity cAMP-specific PDE (Km = 0.2 microM) that does not share other properties of the cAMP-specific PDE family, i.e. extensive sequence homology to the Drosophila dunce cAMP PDE and sensitivity to rolipram and R020-1724 [13].
• Benzothiadiazine 16, although less potent at PDE 7 (IC(50) = 25 microM), also showed a trend of selectivity toward PDE 3 and PDE 4 [14].
• By in situ hybridization histochemistry we have determined the expression pattern of two newly described cAMP-specific phosphodiesterases families, PDE7 and PDE8, in several brain areas in control subjects [15].
• The CD spectra of the polyheptapeptides TM-8, TM-15, and TM-22 show large increases in molar ellipticity at 220 nm on the addition of trifluoroethanol (helix-inducing solvent) to the benign buffer [16].

Other interactions of PDE7A

• Further analysis of MTG/PDE association illustrated that PDE4A and PDE7A bind residues 1-344 of MTG16b [17].
• Confocal analysis of HuT 78 cells stained with anti-PDE7A showed overlapping staining patterns with the Golgi marker GM130, suggesting that PDE7A is located in the Golgi [17].
• Qualitative RT-PCR identified transcripts for PDE4A10, PDE4A7, PDE4B1, PDE4B2, PDE4D1, and PDE4D2 isoforms as well as transcripts for both PDE3B and PDE7A in T cells, monocytes, and macrophages in all subjects [18].
• Interestingly, the relative V(max) value of recombinant PDE7B was half to one-third of recombinant PDE7A [19].
• Further analysis by RT-PCR of the PDE4D and PDE7A splice variants gave different accumulation patterns which may indicate that differential splicing has a role in the regulation of these enzymes [20].

Analytical, diagnostic and therapeutic context of PDE7A

• The staining pattern of PDE7A also showed similarity to the staining pattern of MTG, supporting the immunoprecipitation data and suggesting that MTG may interact with PDE7A in the Golgi [17].
• Northern blot analysis indicates that high levels of HCP1 mRNA are present in human skeletal muscle [13].
• The PDE7A1 (HCP1) isozyme is detected on Western blots as a band with an apparent mobility of 57 kDa, demonstrating that the previously isolated HCP1 cDNA encodes the full-length PDE7A1 protein [9].
• The peptides TM-8, TM-15, and TM-22 were shown to be monomeric in both denaturant (8 M urea) and benign medium by gel-filtration high-performance liquid chromatography on TSK G2000 SW while peptides TM-29 and TM-36 were shown to be dimeric in benign medium both by gel-filtration and sedimentation equilibrium experiments [16].
• Using quantitative real-time PCR, we examined the expression of Hcp1 and other intestinal iron-transporting proteins in male C57BL/6 mice with experimentally altered iron homeostasis [4].

References