Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pentoxifylline (PTX) is a phosphodiesterase inhibitor used in the treatment of peripheral vascular disease, and this agent can suppress inflammatory vascular damage. Inflammation has been implicated in vascular lesion formation, and we examined the effects of PTX in a model of arterial injury. Sprague-Dawley rats were treated with intraperitoneal PTX (75 mg/kg/day) or saline starting 3 days before carotid balloon injury, and killed 24 h or 14 days later. Carotid arteries were analyzed by cross-sectional morphometry, immunostaining for proliferating cell nuclear antigen (PCNA) and subjected to terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL). Moreover, the effects of PTX on vascular smooth-muscle cell (VSMC) migration and production of collagen types I, IV, and VI were examined in vitro. At 14 days after balloon injury, PTX reduced the neointimal area (0.074+/-0.001 vs. 0.172+/-0.003 mm2; p<0.001), media area (0.143+/-0.001 vs. 0.176+/-0.001 mm2; p<0.01), intima/media ratio (0.50+/-0.02 vs. 0.99+/-0.12; p<0.001), and total vessel area (0.601+/-0.010 vs. 0.744+/-0.011 mm2; p<0.01). The lumen area, PCNA expression, and TUNEL were similar in the two treatment groups, whereas the neointimal cell density was increased by PTX (3,476+/-504 cells/mm2 vs. 2,215+/-232 cells/mm2; p<0.05). In vitro, PTX inhibited VSMC production of collagen type I in a concentration-dependent manner and did not influence VSMC migration. We conclude that PTX inhibits neointimal formation and induces constrictive vascular remodeling in the rat model of balloon injury by mechanisms involving decreased VSMC collagen type I production.
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PMID:Pentoxifylline inhibits neointimal formation and stimulates constrictive vascular remodeling after arterial injury. 1054 84

The Apn2 protein of Saccharomyces cerevisiae contains 3'-->5' exonuclease and 3'-phosphodiesterase activities, and these activities function in the repair of DNA strand breaks that have 3'-damaged termini and which are formed in DNA by the action of oxygen-free radicals. Apn2 also has an AP endonuclease activity and functions in the removal of abasic sites from DNA. Here, we provide evidence for the physical and functional interaction of Apn2 with proliferating cell nuclear antigen (PCNA). As indicated by gel filtration and two-hybrid studies, Apn2 interacts with PCNA both in vitro and in vivo and mutations in the consensus PCNA-binding motif of Apn2 abolish this interaction. Importantly, PCNA stimulates the 3'-->5' exonuclease and 3'-phosphodiesterase activities of Apn2. We have examined the involvement of the interdomain connector loop (IDCL) and of the carboxy-terminal domain of PCNA in Apn2 binding and found that Apn2 binds PCNA via distinct domains dependent upon whether the binding is in the absence or presence of DNA. In the absence of DNA, Apn2 binds PCNA through its IDCL domain, whereas in the presence of DNA, when PCNA has been loaded onto the template-primer junction by replication factor C, the C-terminal domain of PCNA mediates the binding.
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PMID:Stimulation of 3'-->5' exonuclease and 3'-phosphodiesterase activities of yeast apn2 by proliferating cell nuclear antigen. 1219 46

Proliferation of oligodendrocyte progenitor (OP) cells is a crucial process controlling myelination in the CNS. Previous studies demonstrated a correlation between OP proliferation rate and cyclin E/cyclin-dependent kinase-2 (cdk2) activity. To establish a causal link between cyclin E/cdk2 activity and OP proliferation, we selectively modulated cdk2 activity in vitro by transfection of cultured OP cells. Dominant-negative (Dn)-cdk2 overexpression inhibited mitogen-induced OP cell proliferation, whereas wild-type (wt)-cdk2 prevented cell cycle arrest caused by anti-mitotic signals. Dn-cdk2- or wt-cdk2-mediated regulation of G(1)/S transition, per se, did not influence initiation of OP differentiation. To study the function of cyclin E/cdk2 in OP cells during development in vivo, we analyzed cdk2 and cyclin E expression in cells acutely isolated from transgenic mice expressing the green fluorescent protein (GFP) under the control of the 2'-3'-cyclic nucleotide 3'-phosphodiesterase gene promoter. Both cyclin E/cdk2 protein levels and activity were decreased in GFP(+) oligodendrocyte lineage cells between postnatal days 4 and 30. Immunostaining of NG2(+)/GFP(+) OP cells in brain tissue sections showed a 90% decrease in overall cell proliferation and cdk2 expression between perinatal and adult cells. However, cdk2 expression within the proliferating (i.e., expressing the proliferating cell nuclear antigen) OP cell population was maintained throughout development. Our data indicate that: (1) cyclin E/cdk2 activity plays a pivotal function in OP cell cycle decisions occurring at G(1)/S checkpoint; (2) initiation of OP differentiation is independent of cyclinE/cdk2 checkpoint, and (3) intrinsic differences in cyclin E/cdk2 expression and activity may underlie the slowly proliferative state that characterizes so-called "quiescent" adult OP cells in vivo.
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PMID:Cyclin-dependent kinase-2 controls oligodendrocyte progenitor cell cycle progression and is downregulated in adult oligodendrocyte progenitors. 1235 29

Neointimal formation, the leading cause of restenosis, is caused by proliferation of vascular smooth muscle cells (VSMCs). Patients with diabetes mellitus have higher restenosis rates after coronary angioplasty than nondiabetic patients. Cilostazol, a selective type 3 phosphodiesterase inhibitor, is currently used to treat patients with diabetic vascular complications. Cilostazol is a potent antiplatelet agent that inhibits VSMC proliferation. In the present study, we examine whether the antiproliferative effect of cilostazol on VSMCs is mediated by inhibition of an important cell cycle transcription factor, E2F. Cilostazol inhibited the proliferation of human VSMCs in response to high glucose in vitro and virtually abolished neointimal formation in rats subjected to carotid artery injury in vivo. Moreover, the compound suppressed high-glucose-induced E2F-DNA binding activity, and the expression of E2F1, E2F2, cyclin A, and PCNA proteins. These data suggest that the beneficial effects of cilostazol on high-glucose-stimulated proliferation of VSMCs are mediated by the downregulation of E2F activity and expression of its downstream target genes, including E2F1, E2F2, cyclin A, and PCNA.
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PMID:Cilostazol inhibits vascular smooth muscle cell growth by downregulation of the transcription factor E2F. 1572 65

Cardiovascular complications are the leading cause of morbidity and mortality in autosomal dominant polycystic kidney disease. Pkd2+/- vascular smooth muscle cells (VSMCs) have an abnormal phenotype and defective intracellular Ca2+ ([Ca2+]i) regulation. We examined cAMP content in vascular smooth muscles from Pkd2+/- mice because cAMP is elevated in cystic renal epithelial cells. We found cAMP concentration was significantly increased in Pkd2+/- vessels compared with wild-type vessels. Furthermore, reducing the wild-type VSMC [Ca2+]i by Verapamil or BAPTA-AM significantly increased cellular cAMP concentration (mainly by phosphodiesterase [PDE] inhibition), the rate of VSMC proliferation (determined by direct cell counting, 3H-incorporation, FACS analysis of cells entering S phase, and quantitative Western PCNA and ERK1/2 analyses), and the rate of apoptosis (by Hoechst staining, FACS analysis of the Annexin-V positive cells, and quantitative Western Bax, cytochrome c, and activated caspase 9 and 3 analyses). The low [Ca2+]i induced VSMC proliferation was independent of cAMP/B-Raf signaling, while that of apoptosis was promoted by cAMP. In summary, Pkd2+/- VSMCs have elevated cAMP levels. This elevation can also be induced by reducing [Ca2+]i in wild-type VSMCs. The [Ca2+]i reduction and cAMP accumulation can cause an increase in both cellular proliferation and apoptosis, resembling Pkd mutant phenotype.
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PMID:[Ca2+]i reduction increases cellular proliferation and apoptosis in vascular smooth muscle cells: relevance to the ADPKD phenotype. 1579 Sep 56

The reaction responsible for replication error correction by mismatch repair proceeds via several steps: mismatch recognition, mismatch-provoked excision, repair DNA synthesis, and ligation. Key steps in this process are the recognition and subsequent exonucleolytic removal of the mispair. A minimal system comprised of human MutSalpha (MSH2*MSH6), MutLalpha (MLH1*PMS2), exonuclease I (EXOI), replication protein A (RPA), proliferating cell nuclear antigen (PCNA), and replication factor C (RFC) is sufficient to support mismatch-provoked excision in vitro. This chapter describes methods for analysis of the reconstituted excision reaction.
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PMID:Analysis of the excision step in human DNA mismatch repair. 1679 75

Half of hereditary nonpolyposis colon cancer kindreds harbor mutations that inactivate MutLalpha (MLH1*PMS2 heterodimer). MutLalpha is required for mismatch repair, but its function in this process is unclear. We show that human MutLalpha is a latent endonuclease that is activated in a mismatch-, MutSalpha-, RFC-, PCNA-, and ATP-dependent manner. Incision of a nicked mismatch-containing DNA heteroduplex by this four-protein system is strongly biased to the nicked strand. A mismatch-containing DNA segment spanned by two strand breaks is removed by the 5'-to-3' activity of MutSalpha-activated exonuclease I. The probable endonuclease active site has been localized to a PMS2 DQHA(X)(2)E(X)(4)E motif. This motif is conserved in eukaryotic PMS2 homologs and in MutL proteins from a number of bacterial species but is lacking in MutL proteins from bacteria that rely on d(GATC) methylation for strand discrimination in mismatch repair. Therefore, the mode of excision initiation may differ in these organisms.
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PMID:Endonucleolytic function of MutLalpha in human mismatch repair. 1687 53

A second class II AP endonuclease, APEX2, possesses strong 3'-5' exonuclease and 3'-phosphodiesterase activities but only very weak AP-endonuclease activity. APEX2 associates with proliferating cell nuclear antigen (PCNA), and the progression of S phase of the cell cycle is accompanied by its expression. APEX2-null mice exhibit severe dyslymphopoiesis in thymus as well as moderate dyshematopoiesis and growth retardation. Comparative gene expression profiling of wild-type and APEX2-null mice using an oligonucleotide microarray revealed that APEX2-null thymus has significantly altered gene expression profiles, reflecting its altered populations of thymocytes. Beyond these altered populations, APEX2-null thymus exhibits significant alterations in expression of genes involved in DNA replication, recombination and repair, including Apex1, Exo1 and Fen1 as well as master genes for the DNA damage response, such as E2f1, Chek1, and proapoptotic genes. We therefore examined the extent of DNA strand breakage, and found that both of single-strand breaks detected as comets and double-strand breaks detected as gammaH2AX foci were significantly higher in frequency in most APEX2-null thymocytes compared to wild-type thymocytes. This higher frequency of DNA breaks was accompanied by increased expression of PCNA and increased phosphorylation of p53 at Ser23 and to a lesser extent, at Ser18. The present study clearly demonstrates that APEX2-null lymphocytes have a higher frequency of DNA breaks, indicating that APEX2 may play an important role(s) during their generation and/or repair.
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PMID:Altered gene expression profiles and higher frequency of spontaneous DNA strand breaks in APEX2-null thymus. 1858 82

Flap endonuclease-1 (FEN1) is a structure specific endonuclease. The natural substrates of FEN1 are 5'-flap structures formed by three DNA chains one of them has unannealed flapped 5'-end (flap). Flap structures are the intermediates of different processes of DNA metabolism, such as DNA recombination, Okazaki fragment maturation during replication of lagging strand, as well as strand displacement DNA synthesis in base excision repair. FEN1 also possesses 5'-exonuclease activity and newly discovered gap endonuclease activity. FEN1 is known to interact physically and functionally with a number of DNA replication and repair proteins such as the proliferating cell nuclear antigen, helicase/nuclease Dna2, WRN and BLM proteins, replication protein A, apurinic/apyrimidinic endonuclease 1, DNA polymerase beta, poly(ADP-riboso) polymerase 1, high mobility group protein 1, integrase of human immunodeficiency virus, transcription coactivator p300, chromatin proteins, cyclin-dependent kinases (Cdk1, Cdk2, Cyclin A). FEN1 activity is significant for maintaining the integrity of repeat sequences in genome. Recent data suppose the correlation between the abnormality of hFEN1 activity and arising/progression of neurodegenerative and cancer diseases. FEN1 has the dramatic effect on cell growth and development thereby attracting the interest to this enzyme.
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PMID:[Flap endonuclease-1 and its role in the processes of DNA metabolism in eucaryotic cells]. 1870 99

Human Ape2 protein has 3' phosphodiesterase activity for processing 3'-damaged DNA termini, 3'-5' exonuclease activity that supports removal of mismatched nucleotides from the 3'-end of DNA, and a somewhat weak AP-endonuclease activity. However, very little is known about the role of Ape2 in DNA repair processes. Here, we examine the effect of interaction of Ape2 with proliferating cell nuclear antigen (PCNA) on its enzymatic activities and on targeting Ape2 to oxidative DNA lesions. We show that PCNA strongly stimulates the 3'-5' exonuclease and 3' phosphodiesterase activities of Ape2, but has no effect on its AP-endonuclease activity. Moreover, we find that upon hydrogen-peroxide treatment Ape2 redistributes to nuclear foci where it colocalizes with PCNA. In concert with these results, we provide biochemical evidence that Ape2 can reduce the mutagenic consequences of attack by reactive oxygen species not only by repairing 3'-damaged termini but also by removing 3'-end adenine opposite from 8-oxoG. Based on these findings we suggest the involvement of Ape2 in repair of oxidative DNA damage and PCNA-dependent repair synthesis.
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PMID:Role of PCNA-dependent stimulation of 3'-phosphodiesterase and 3'-5' exonuclease activities of human Ape2 in repair of oxidative DNA damage. 1944 50


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