Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abetalipoproteinemia is a rare genetic disease that has provided important new insights into the physiology of lipoprotein assembly and vitamin E metabolism. Forty-two years after its initial description, a molecular etiology of ABL has been reported to be a deficiency of a microsomal transfer protein, thus suggesting that this protein plays a key role in lipoprotein particle assembly and secretion both in the intestine and in the liver. Furthermore, studies in patients with ABL have established the critical role of hepatic secretion of VLDL in the delivery of vitamin E to peripheral tissues and the essential role of vitamin E in the maintenance of normal physiological function of multiple tissues. The systematic investigation of this rare genetic disease has provided insights that have substantially enhanced our understanding of human physiology.
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PMID:Abetalipoproteinemia. New insights into lipoprotein assembly and vitamin E metabolism from a rare genetic disease. 834 Sep 87

The hybrid gene BCR-ABL that typifies chronic myeloid leukemia (CML) represents an attractive target for therapy with antisense oligodeoxyribonucleotides (ODN). A central obstacle in the therapeutic application of ODN is their poor cellular uptake. Adding various lipophilic conjugates to the ODN backbone has been reported to improve uptake, and electroporation of target cells has also been shown to enhance intracellular ODN delivery. We have shown that (1) BCR-ABL-directed ODN will specifically decrease the level of BCR-ABL mRNA, provided that cells are first permeabilized with Streptolysin-O (SL-O), and (2) chimeric methylphosphonodiester:phosphodiester ODN directed against 9 bases either side of the BCR-ABL junction are more efficient ODN effectors than structures composed solely of phosphodiester or phosphorothioate linkages. In this study, we compared the efficacy of lipophilic conjugation, SL-O permeabilization and electroporation on the intracellular delivery and molecular effect of BCR-ABL-directed ODN. b2a2- and b3a2-directed chimeric ODN were synthesized either unmodified or with one of the following groups at the 5' end: cholesterol, vitamin E, polyethylene glycol of average molecular weight 2,000 or 5,000, N-octyl-oligo-oxyethylene, or dodecanol. ODN associated with Lipofectin was also studied. Comparison was made in untreated, electroporated, and SL-O permeabilized KYO1 cells. Uptake was examined by fluorescence microscopy and flow cytometry, using ODN structures that were 3' labeled with fluorescein. The effect on target BCR-ABL mRNA expression was analyzed by Northern blotting. Several conjugated structures associated avidly with the cell membrane without achieving significant intracellular uptake or molecular effect. Similarly, ODN:Lipofectin complexes moderately increased cell association, without enhancing intracellular levels of ODN or inducing detectable molecular effect. In SL-O permeabilized or electroporated cells, uptake was approximately 1 to 2 logs greater than in untreated cells, and rapid nuclear localization was seen, especially with unmodified chimeric ODN. In SL-O permeabilized cells treated with ODN directed to the b2a2 and b3a2 junctions respectively, b2a2 BCR-ABL mRNA levels at 4 hours were reduced to 2. 6% +/- 2.1% and 38.4% +/- 1.3% of control values. In cells permeabilized by electroporation, BCR-ABL mRNA levels were decreased to 4.0% +/- 1.4% of control levels by b2a2 directed ODN, although very little nontargeted suppression was seen with b3a2-targeted ODN (93.4% +/- 4.2% of control). Greater cell to cell variation in ODN uptake was seen for SL-O permeabilized cells when compared with electroporated cells, suggesting that, after SL-O permeabilization, relatively unpermeabilized and overpermeabilized populations may coexist. No structure had any effect on the level of irrelevant (p53, MYC, and GADPH) mRNA levels. We conclude that the conjugation of chimeric ODN with one of the above-mentioned lipophilic groups or the complexing of ODN with Liopfectin does not improve either intracellular delivery of ODN or the molecular effect. In contrast, both electroporation and SL-O permeabilization (1) considerably enhanced uptake of chimeric ODN (even for structures without a conjugate group) and (2) achieved significant suppression of target mRNA levels.
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PMID:Improving the intracellular delivery and molecular efficacy of antisense oligonucleotides in chronic myeloid leukemia cells: a comparison of streptolysin-O permeabilization, electroporation, and lipophilic conjugation. 961 72

Atherosclerosis includes a series of cellular and molecular responses characteristic of an inflammatory disease. We provide evidence that cupric-ion-oxidized LDL (CuLDL) or endothelial cell-oxidized LDL (ELDL) induced the activation by Tyr-phosphorylation of JAK2, one of the Janus kinase involved upstream of STATs in the JAK/STAT pathway of cytokine transduction. Oxidized LDL (OxLDL) also initiated STAT1 and STAT3 Tyr-phosphorylation and translocation to the nucleus, with a more marked effect for the extensively modified CuLDL. Genistein, a nonspecific Tyr-kinase inhibitor, and AG490, a specific inhibitor of JAKs, markedly prevented the CuLDL-induced enhancement of STAT1 and STAT3 Tyr-phosphorylation and DNA-binding activity, suggesting that JAKs are the main kinases involved in STATs' activation by oxidized LDL. In addition, the lipid extract of CuLDL increased the intracellular levels of lipid peroxidation products and the Tyr-phosphorylation of JAK2, STAT1, and STAT3, whereas the antioxidant vitamin E prevented all these effects. These results demonstrate that OxLDL induces the activation by Tyr-phosphorylation of JAK2, STAT1, and STAT3 by generation of an intracellular oxidative stress by means of its lipid peroxidation products, and thus include JAK2 within the range of oxidative stress-activated kinases.
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PMID:Activation of JAK2 by the oxidative stress generated with oxidized low-density lipoprotein. 1172 4

The effects of four natural tocopherols on the proliferation and signaling pathways were examined in the human mastocytoma cell line (HMC-1). The four tocopherols inhibited HMC-1 cell proliferation with different potency (delta > alpha = gamma > beta). Growth inhibition correlated with the reduction of PKB (protein kinase B) phosphorylation by the different tocopherols. The reduction of PKB phosphorylation led to a decrease of its activity, as judged from a parallel reduction of GSKalpha/beta phosphorylation. The translocation of PKB to the membrane, as a response to receptor stimulation by NGFbeta, is also prevented by treatment with tocopherols. In the presence of PKC or PP2A inhibitors, the reduction of PKB phosphorylation by tocopherols was still observed, thus excluding the direct involvement of these enzymes. Other pathways, such as the Ras-stimulated ERK1/2 (extracellular signal responsive kinase) pathway, were not affected by tocopherol treatment. The tocopherols did not significantly change oxidative stress in HMC-1 cells, suggesting that the observed effects are not the result of a general reduction of oxidative stress. Thus, the tocopherols interfere with PKB phosphorylation and reduce proliferation of HMC-1 cells, possibly by modulating either phosphatidylinositol 3-kinase, a kinase phosphorylating PKB (PDK1/2), or a phosphatase that dephosphorylates it. Inhibition of proliferation and PKB signaling in HMC-1 cells by vitamin E suggests a role in preventing diseases with mast cell involvement, such as allergies, atherosclerosis, and tumorigenesis.
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PMID:Inhibition of HMC-1 mast cell proliferation by vitamin E: involvement of the protein kinase B pathway. 1538 41

Life-threatening proinflammatory response (PR) induces severe GH resistance. Although low-level PR is much more commonly encountered clinically, relatively few studies have investigated the accompanying change in GH signal transduction progression and, in particular, the impact of low-level PR on Janus kinase (JAK)-2. Using a low-level, in vivo endotoxin [lipopolysaccharide (LPS)] challenge protocol, we demonstrated that the liver tissue content of JAK2 declined 24 h (62%, P < 0.02) after LPS and that tyrosine-nitrated JAK2 could be immunoprecipitated from post-LPS liver biopsy homogenates. With antibodies developed to probe specifically for nitration at the (1007)Y-(1008)Y phosphorylation epitope of JAK2, we demonstrated that the nitrated (1007)Y-(1008)Y-JAK-2 (nitro-JAK2) coimmunoprecipitated with caveolin-1 and (1177)phospho-SER-endothelial nitric oxide synthase when post-LPS liver homogenates were treated with anticaveolin-1 and protein A/G. The magnitude of increase in nitro-JAK2 was attenuated in animals treated with vitamin E prior to LPS. The increase in nitro-JAK2 after LPS was greater in a line of experimental animals with a genetic propensity for higher PR at the given LPS dose than responses measured in their normal counterparts. The development and remission of nitro-JAK2 was temporally concordant with changes in plasma concentrations of IGF-I; hepatocellular IGF-I mRNA content was inversely proportional to nitro-JAK2 content. Localized changes in the state of nitration of regulatory phosphorylation domains of JAK2 in caveolar microenvironments and tissue content of JAK2 during PR suggest a unique mechanism through which discrete signal transduction switching might occur in the liver to fine tune cellular responses to the endocrine-immune signals that develop during low-level, transient proinflammatory stress.
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PMID:Caveolae nitration of Janus kinase-2 at the 1007Y-1008Y site: coordinating inflammatory response and metabolic hormone readjustment within the somatotropic axis. 1751 Feb 31

Abetalipoproteinemia (ABL, OMIM 200100) is a rare, autosomal recessive disorder, characterized by fat malabsorption, acanthocytosis and hypocholesterolemia in infancy. Later in life, deficiency of fat-soluble vitamins is associated with development of atypical retinitis pigmentosa, coagulopathy, posterior column neuropathy and myopathy. ABL results from mutations in the gene encoding the large subunit of microsomal triglyceride transfer protein (MTP; OMIM 157147). To date at least 33 MTP mutations have been identified in 43 ABL patients. We describe the clinical progress of two patients, both currently in the fifth decade of life, who were diagnosed with ABL as children and were treated with high oral doses of fat soluble vitamins, including vitamin E over the last three decades. Treatment appears to have been associated with arrest of the neuropathy and other complications in both patients. Because pharmacologic inhibition of MTP is being developed as a novel approach to reduce plasma cholesterol for prevention of cardiovascular disease, defining the long-term clinical features of patients with a natural deficiency in MTP might provide some insight into the possible effects of such treatments. We review the range of clinical, biochemical and molecular perturbations in ABL.
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PMID:Abetalipoproteinemia: two case reports and literature review. 1861 Dec 56

Abetalipoproteinemia (ABL; OMIM 200100) is an inherited disorder resulting from mutations in the microsomal triglyceride transfer protein gene and characterized by a major lipid malabsorption leading to extremely low plasma cholesterol and triglyceride levels and fat-soluble vitamins deficiencies. We report two novel mutations (c.59del17 and c.582C>A) and the long-term follow-up of four ABL subjects treated with vitamin E. The good outcome of the early-treated patients contrasts with severe ataxia and retinopathy observed in the patient with delayed treatment. In conclusion, early diagnosis and early management are essential to prevent the manifestations following the fat-soluble vitamin deficiencies.
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PMID:Identification of two novel mutations and long-term follow-up in abetalipoproteinemia: a report of four cases. 1906 57

Cholesterol oxides, in particular 7-ketocholesterol, are proatherogenic compounds that induce cell death in the vascular wall when localized in lipid raft domains of the cell membrane. Deleterious effects of 7-ketocholesterol can be prevented by vitamin E, but the molecular mechanism involved is unclear. In this study, unlike gamma-tocopherol, the alpha-tocopherol vitamin E form was found to prevent 7-ketocholesterol-mediated apoptosis of A7R5 smooth muscle cells. To be operative, alpha-tocopherol needed to be added to the cells before 7-ketocholesterol, and its anti-apoptotic effect was reduced and even suppressed when added together or after 7-ketocholesterol, respectively. Both pre- and co-treatment of the cells with alpha-tocopherol resulted in the redistribution of 7-ketocholesterol out of the sphingolipid/cholesterol-enriched (lipid raft) domains. In turn, fewer amounts of alpha-tocopherol associated with lipid rafts on 7-ketocholesterol-pretreated cells compared with untreated cells, with no prevention of cell death in this case. In further support of the implication of lipid raft domains, the dephosphorylation/inactivation of Akt-PKB was involved in the 7-ketocholesterol-induced apoptosis. Akt-PKB dephosphorylation was prevented by alpha-tocopherol, but not gamma-tocopherol pretreatment.
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PMID:7-ketocholesterol incorporation into sphingolipid/cholesterol-enriched (lipid raft) domains is impaired by vitamin E: a specific role for alpha-tocopherol with consequences on cell death. 1935 82

The objective was to determine the effects of natural- or synthetic-source vitamin E on reproductive efficiency in Angus-cross beef cows. In Exp. 1, one hundred fifty-two cows were fed hay and corn silage based diet and assigned to 1 of 3 dietary supplements (3 pens/treatment): 1) containing no additional vitamin E (CON), 2) formulated to provide 1,000 IU x d(-1) of synthetic-source vitamin E (SYN; all-rac or dl-alpha-tocopherol acetate), or 3) formulated to provide 1,000 IU x d(-1) of natural-source vitamin E (NAT; RRR or D-alpha-tocopherol acetate). In Exp. 2, seventy-five cows (2 reps/treatment) were assigned to similar treatments as Exp. 1; however, a vitamin-mineral supplement was offered for ad libitum intake and vitamin intake was calculated from predicted mineral intakes. Cows grazed pastures rather than being fed hay and corn silage as in Exp. 1. In Exp. 1 and 2, supplementation began 6 wk prepartum and continued until initiation of the breeding season. Blood samples were collected at calving (Exp. 1) or breeding (Exp. 2) to determine alpha-tocopherol concentration and weekly beginning 4 wk postpartum (Exp. 1) or 7 and 14 d before estrus synchronization (Exp. 2) to determine return to estrus via progesterone concentration. Cows were synchronized and bred by AI based on heat detection; nonresponding cows were time bred (AI) 66 h after PGF(2 alpha) injection, and cows returning to estrus after AI were bred by natural service. In Exp. 1, cows supplemented with NAT and SYN had greater (P < 0.001) serum concentrations of alpha-tocopherol at calving compared with CON cows. Dietary supplement did not affect (P >or= 0.55) the percentage of cows cycling before synchronization or the number of days to return to estrus by cows that resumed estrus before synchronization. Cows supplemented with SYN tended to have greater first service conception rates compared with CON and NAT (P = 0.09); however, first plus second services combined and overall conception rates were not affected (P >or= 0.23). In Exp. 2, NAT cows had greater (P = 0.002) concentrations of alpha-tocopherol at breeding, whereas there was no difference (P > 0.05) between SYN and CON. Supplementation of SYN or NAT did not affect (P >or= 0.17) days to resumption of estrus before breeding, first service, first plus second services combined, or overall conception rates. These data suggest that supplementation of SYN or NAT source vitamin E increased alpha-tocopherol concentration in cows; however, effects on reproductive efficiency are minimal.
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PMID:Effects of natural (RRR alpha-tocopherol acetate) or synthetic (all-rac alpha-tocopherol acetate) vitamin E supplementation on reproductive efficiency in beef cows. 2049 21

Abnormal proliferation of vascular smooth muscle cells (VSMCs) plays an important role in the development of cardiovascular diseases. PMC (2,2,5,7,8-pentamethyl-6-hydroxychromane) is the most potent hydrophilic derivative of vitamin E. In this study, we investigated the mechanisms of PMC inhibition of VSMC proliferation in vitro and in vivo. PMC (20 and 50 microM) obviously suppressed proliferation of PDGF-BB-stimulated cells, but not resting cells, and arrested cell cycle progression at the G(2)/M phase. A significant reduction in neointimal formation in carotid arteries was observed in PMC (5mg/kg/day)-treated rats after balloon angioplasty. Activation of STAT3, JAK2, PLCgamma1, PKCdelta, and ROS, but not ERK1/2, AKT, or PKCalpha, was markedly inhibited by PMC in PDGF-BB-stimulated VSMCs. Deferoxamine and PMC significantly inhibited the phosphorylation of PLCgamma1 and JAK2 and arrested cell cycle progression at the G(2)/M phase. These events, however, were reversed in the presence of Fe(2+). Moreover, PMC directly inhibited hydroxyl radical formation in both the Fenton reaction and VSMCs according to an electron spin resonance study. In conclusion, this study demonstrates for the first time that PMC inhibits VSMC proliferation in vitro and balloon injury-induced neointimal formation in vivo. The inhibitory mechanism of PMC may involved the inhibition of hydroxyl radical-mediated PLCgamma1-PKCdelta and JAK2-STAT3 activation and causes cell cycle arrest at the G(2)/M phase. PMC treatment may represent a novel approach for lowering the risk of or improving function in abnormal VSMC proliferation-related vascular diseases.
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PMID:Inhibition of vascular smooth muscle cell proliferation by the vitamin E derivative pentamethylhydroxychromane in an in vitro and in vivo study: pivotal role of hydroxyl radical-mediated PLCgamma1 and JAK2 phosphorylation. 2060 Aug 39


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