Disease relevance of PI3

• Our findings indicate that elafin and SLPI may be gene therapy targets for the treatment of atheroma [1].
• We recently described the isolation of elafin from bronchial secretions, a new elastase-specific inhibitor that is also found in the skin of patients with psoriasis [2].
• Elafin-overexpressing mice have improved cardiac function after myocardial infarction [3].
• CD3/CD28-induced activation of the PI3/Akt kinase pathway and proliferation is impaired in T cells after contact with the measles virus (MV) glycoprotein (gp) complex [4].
• The phosphoinositol 3 kinase (PI3 K)/Akt and the nuclear factor kappaB (NF-kappaB) pathways control both proliferation and resistance to apoptosis of pancreatic cancer [5].

Psychiatry related information on PI3

• ESI Cognitive Orientation Toward Spirituality significantly correlated with Complex Partial Epileptic-like Signs but it was not a significant predictor in regression analyses [6].

High impact information on PI3

• Here we report that, in addition to PI-3' kinase activity, anti-phosphotyrosine (alpha-P-tyr) immunoprecipitates from platelet-derived growth factor (PDGF)-stimulated smooth muscle cells (SMC) contain lipid kinase activities that utilize the substrates phosphatidylinositol-4-phosphate (PI-4-P) and phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) [7].
• These results demonstrate that the PI 3-kinase-Akt signaling pathway, in concert with FRAP/mTOR, induces the phosphorylation of 4E-BP1 [8].
• Here we demonstrate in CD4(+) T cells that CpG DNA directly enhances proliferation, prevents anergy, and augments humoral responses to a T cell-dependent antigen by a Myeloid differentiation primary-response protein 88 (MyD88) and Phosphatidylinositol 3-kinase (PI-3 kinase)-dependent pathway [9].
• To investigate this, we showed that wire-induced endothelial denudation of the carotid artery is associated with transient elevation in elastase activity and confirmed that this is abolished in transgenic mice overexpressing the serine elastase inhibitor, elafin, targeted to the cardiovascular system [10].
• To distinguish the transgene from endogenous elafin, constructs were made incorporating a FLAG sequence; the COOH-terminus FLAG-tagged elafin construct produced a stable, functionally active gene product and was used to create transgenic mice [11].

Chemical compound and disease context of PI3

• We therefore assessed the effects of overexpressing the selective serine elastase inhibitor elafin in transgenic mice in which a myocardial infarction was caused by ligation of the left anterior descending coronary artery (LAD) [3].
• Here we show that the mobilization of intracellular calcium, which follows crosslinking of MHC-I molecules on human B lymphoma cells, is dependent on protein tyrosine kinases and the phosphatidylinositol 3 (PI-3) kinase [12].
• We measured the effect of these detergents on direct cellular toxicity (lactate dehydrogenase release), on the expression of markers for normal differentiation (cytokeratin 1 and involucrin expression), and on disturbed keratinocyte differentiation (SKALP) by northern blot analysis [13].
• Levels of skin-derived antileukoproteinase (SKALP)/elafin in serum correlate with disease activity during treatment of severe psoriasis with cyclosporin A [14].
• ESI/MST/MS of model compounds found characteristic water loss from alcohol dehydration and anhydride formation, as well as CO2 loss from decarboxylation, and CO loss from ester structures [15].

Biological context of PI3

• This region could therefore be the reactive site of ESI [16].
• Purification and characterization of elastase-specific inhibitor. Sequence homology with mucus proteinase inhibitor [16].
• The coding information for a 117 amino acid precursor protein of elafin (inclusive of the signal peptide) is contained in the first two exons [17].
• In summary, progesterone has a differential effect on SLPI and elafin expression and although both vary within the uterus throughout the menstrual cycle, progesterone is likely to contribute to the direct regulation of SLPI in the female reproductive tract even in the presence of inflammatory agents [18].
• Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors [19].

Anatomical context of PI3

• Adenoviral gene delivery of elafin and secretory leukocyte protease inhibitor attenuates NF-kappa B-dependent inflammatory responses of human endothelial cells and macrophages to atherogenic stimuli [1].
• We showed in addition that epithelial cell lines produce the elastase-specific inhibitor as a 12 to 16 kD precursor of the elafin molecule (6 kD) called pre-elafin [20].
• In the present study, we show that NCI-H322 cells produced higher amounts of both inhibitors than A549 cells and that basal production of SLPI in both cell lines is higher than the production of elafin/pre-elafin [20].
• Skin-derived antileukoproteinase (SKALP), an elastase inhibitor from human keratinocytes. Purification and biochemical properties [21].
• Elafin and its precursor trappin-2 (also called pre-elafin) are potent protein inhibitors of neutrophil serine proteases such as leukocyte elastase and proteinase 3 [22].

Associations of PI3 with chemical compounds

• The elafin molecule, a 6.0 kD inhibitor of serine proteinases shows homology with mucus proteinase inhibitor [17].
• In contrast, progesterone treatment has no direct effect on elafin mRNA expression [18].
• This insulin resistance was associated with impaired insulin receptor substrate (IRS)-2-associated phosphatidylinositol 3' (PI3) kinase activation and IRS-2 tyrosine phosphorylation as well as significantly decreased protein kinase C (PKC)-zeta/lambda activation in response to insulin [23].
• Furthermore, treatment with 10 microM of phosphatidylinositol 3 (PI3) kinase inhibitor, LY294002, abrogates HGF-induced cell scattering of SHIP-2-overexpressing cells but not parental HEK293 cells, suggesting that a balance between PI3 kinase and SHIP is important for cell motility [24].
• Thus, engagement of membrane estrogen receptors results in rapid endothelial NO release through a PI3-kinase-Akt-dependent pathway [25].
• NE in excess was shown to strongly diminish the ability of elafin to bind lipopolysaccharide (LPS) and its capacity to be immobilized by transglutamination [26].

Physical interactions of PI3

• Loss of the DNA binding domain did not change E2 activation of Src or erk, but ligand-induced PI3 kinase-ERalpha binding and eNOS phosphorylation did not occur [27].
• Skin-derived antileukoproteinase (SKALP) and epidermal fatty acid-binding protein (E-FABP): two novel markers of the psoriatic phenotype that respond differentially to topical steroid [28].

Enzymatic interactions of PI3

• Correspondingly, the association between phosphatidyl-inositol 3 (PI3) kinase and phosphorylated IRS-1 was reduced in PNET1 compared with PNET2 cells [29].
• Artemis protein is phosphorylated in a PI3-like kinase-dependent manner after either IR or a number of other DNA damaging treatments including etoposide, but SCIDA cells are not hypersensitive to treatment with etoposide [30].

Co-localisations of PI3

• Double staining demonstrated that elafin was co-localized with tTG [31].

Regulatory relationships of PI3

• The protection by IGF-1 is inhibited by the phosphoinositide 3-OH (PI 3) kinase inhibitor, wortmannin [32].
• PTEN is a tumor suppressor gene encoding a phosphatase that negatively regulates cell survival mediated by the PI3-kinase-Akt pathway [33].
• EGFR enhances Survivin expression through the phosphoinositide 3 (PI-3) kinase signaling pathway [34].
• Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the PI3-kinase-Akt pathway in human endothelial cells [25].
• Topical application of EGF further stimulates the activity and expression of PI 3- kinase [35].

Other interactions of PI3

• In addition, we show that interleukin-1 beta and tumor necrosis factor induce significant SLPI expression and are major inducers of elafin/pre-elafin expression [20].
• The thermodynamic and kinetic constants of the reactions of ESI with human neutrophil elastase and with porcine pancreatic elastase show that ESI is a fast-acting inhibitor [16].
• VEGF has been shown to mediate this additional function, at least in part through the induction of bcl-2 and the activation of the PI3 kinase-Akt/PKB signaling pathway [36].
• Transfection with tumor suppressor PTEN cDNA into HT1080 and constitutively active PI 3-kinase-CAAX cDNA into MCH603 cells, respectively, resulted in several interesting and novel observations [37].
• PTEN lipid phosphatase degrades PIP3 and negatively regulates Akt, whereas this is activated by EGFR through PI3 [38].

Analytical, diagnostic and therapeutic context of PI3

• Analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) of cells from lavages and of nucleated cells isolated from the peripheral blood showed the production of ESI only, but not of MPI [39].
• By Northern Blot analysis we detected a 800 bp long product, and by immunoaffinity we detected in sputum and in cultured epithelial cell supernatant (NCI-H322 cell line) a 12 kD protein species cross-reacting with anti-elafin IgG [17].
• Elevated serine elastase activity was observed in nontransgenic littermates as early as 6 h after LAD ligation and persisted at 4 and 7 days but not in sham-operated or elafin-overexpressing transgenic mice [3].
• Intracellular or cell-associated elafin protein accumulated after 24 h of culture only in S. rectivirgula antigen-stimulated alveolar macrophages as shown by Western blot [40].
• In the present study, we showed by RT-PCR that human alveolar macrophages, but not peripheral blood monocytes, express elafin and SLPI transcripts [40].

References