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K Suzuki - One of the best experts on this subject based on the ideXlab platform.

  • Role of Squalene Synthase in prostate cancer risk and the biological aggressiveness of human prostate cancer
    Prostate Cancer and Prostatic Diseases, 2012
    Co-Authors: Y Fukuma, H Matsui, H Koike, Y Sekine, I Shechter, N Ohtake, S Nakata, K Suzuki
    Abstract:

    Background: We previously conducted a genome-wide linkage analysis of Japanese nuclear families affected with prostate cancer and showed that the susceptibility to prostate cancer was closely linked to D8S550 at 8p23. The role of farnesyl diphosphate farnesyltransferase ( FDFT1 ), which is located under the peak marker D8S550 at 8p23, and Squalene Synthase, the enzyme encoded by FDFT1 , in prostate cancer was studied. Methods: The association among common variants of FDFT1 with prostate cancer risk, the promoter activities of FDFT1 with different genotypes and the effects of inhibition of Squalene Synthase were studied, and the FDFT1 transcript levels of human prostate samples were quantified. Results: The A allele of rs2645429 was significantly associated with prostate cancer risk in a Japanese familial prostate cancer population. Rs2645429 was located in the promoter region of FDFT1 , and the AA genotype showed significantly increased promoter activity. The knockdown of FDFT1 mRNA expression or Squalene Synthase inhibition led to a significant decrease in prostate cancer cell proliferation. Additionally, human prostate cancer specimens expressed significantly higher levels of FDFT1 mRNA compared with noncancerous specimens. Finally, aggressive cancers showed higher transcript levels. Conclusions: FDFT1 and its encoded enzyme, Squalene Synthase, may play an important role in prostate cancer development and its aggressive phenotypes.

  • Role of Squalene Synthase in prostate cancer risk and the biological aggressiveness of human prostate cancer.
    Prostate cancer and prostatic diseases, 2012
    Co-Authors: Y Fukuma, H Matsui, H Koike, Y Sekine, I Shechter, N Ohtake, S Nakata, Kazuto Ito, K Suzuki
    Abstract:

    Role of Squalene Synthase in prostate cancer risk and the biological aggressiveness of human prostate cancer

Ishaiahu Shechter - One of the best experts on this subject based on the ideXlab platform.

  • zwitterionic sulfobetaine inhibitors of Squalene Synthase
    Journal of Organic Chemistry, 1999
    Co-Authors: Thomas A. Spencer, Guojian Jiang, Thomas J. Onofrey, Reginald O. Cann, Alfredo Castro, Jonathon S Russel, Laura E Lee, Daniel E Blanchard, Ishaiahu Shechter
    Abstract:

    A substantial number of sulfobetaines (e.g., 10) have been synthesized and evaluated as inhibitors of Squalene Synthase (SS) on the basis of the idea that their zwitterionic structure would have properties conducive both to binding in the active site and to passage through cell membranes. When the simple sulfobetaine moiety is incorporated into compounds containing hydrophobic portions like those in farnesyl diphosphate (1) or preSqualene diphosphate (2), inhibition of SS in a rat liver microsomal assay was indeed observed. For example, farnesylated sulfobetaine 10 has IC50 = 10 μM and aromatic derivative 35 has IC50 = 2 μM for SS inhibition. A wide variety of structural modifications, exemplified by compounds 43, 52, 76, 85, 91, 99, 111, and 115, was investigated. Unfortunately, no inhibitors in the submicromolar range were discovered, and exploration of a different type of zwitterion seems necessary if this appealing approach to inhibition of SS is going to provide a potential antihypercholesterolemic a...

  • ENDOTOXIN, TUMOR NECROSIS FACTOR, AND INTERLEUKIN-1 DECREASE HEPATIC Squalene Synthase ACTIVITY, PROTEIN, AND MRNA LEVELS IN SYRIAN HAMSTERS
    Journal of lipid research, 1997
    Co-Authors: Riaz A. Memon, Ishaiahu Shechter, Arthur H. Moser, Judy K. Shigenaga, Carl Grunfeld, Kenneth R. Feingold
    Abstract:

    Recent studies have shown that endotoxin (LPS) administration to Syrian hamsters markedly increased hepatic HMGCoA reductase activity, protein mass, and mRNA levels, but only produced a modest increase in hepatic cholesterol synthesis, suggesting that LPS may also influence other key enzymes involved in the regulation of cholesterol metabolism. In the present study, we have examined the effect of LPS and cytokines on the activity, protein mass, and mRNA level of' Squalene Synthase, which is the first committed enzyme in chc- lesterol biosynthesis and is located at a branch point in the mevalonate pathway. Our results demonstrate that LPS ad- ministration produces a marked decrease in the mRNA levels of Squalene Synthase. This decrease in Squalene Synthase mRNA occurred very rapidly (90 min after LPS) and required relatively small doses of LPS (1 pg/ 100 gm body weight). LPS also significantly decreased Squalene Synthase activity and pro- tein mass. Finally, LPS produced a marked decrease in squa- lene Synthase mRNA, activity, and protein levels when the basal levels of Squalene Synthase expression were increased 4 fold by prior treatment with bile acid binding resin, colestipol. Tumor necrosis factor and interleukin-1, which mediate many of the metabolic effects of LPS, also decreased hepatic squa- lene Synthase activity and mRNA 1evels.l Taken together, our results suggest that the discordant regulation of HMG CoA reductase and Squalene Synthase during the host re- sponse to infection and inflammation may have substantial effects on the regulation of substrate flux into the non-sterol pathways of mevalonate metabolism.-Memon, R. A., I. Shechter, A. H. Moser, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold. Endotoxin, tumor necrosis factor, and interleukin-1 decrease hepatic Squalene Synthase activity, protein, and mRNA levels in Syrian hamsters.). Lipid Res. 1997. 38: 1620- 1629.

  • SULFOBETAINE ZWITTERIONIC INHIBITORS OF Squalene Synthase
    Bioorganic & Medicinal Chemistry Letters, 1996
    Co-Authors: Ishaiahu Shechter, Guojian Jiang, Thomas J. Onofrey, Reginald O. Cann, Alfredo Castro, Thomas A. Spencer
    Abstract:

    Abstract Zwitterions such as farnesyl sulfobetaine 8 are a new type of inhibitor of Squalene Synthase that, while maintaining overall neutrality, mimic both the carbocationic and anionic moieties of presumed reaction intermediates. The most effective zwitterionic sulfobetaines discovered to date are aromatic derivatives 17 (IC 50 = 2 μM) and 20 (IC 50 = 5 μM).

  • Subcellular localization of Squalene Synthase in rat hepatic cells. Biochemical and immunochemical evidence.
    Journal of Biological Chemistry, 1993
    Co-Authors: K. D. Stamellos, Ishaiahu Shechter, Guojian Jiang, D. G. Conrad, Gilbert-andre Keller, J E Shackelford, Skaidrite K. Krisans
    Abstract:

    Abstract In the present study we investigated the subcellular localization of Squalene Synthase (farnesyl-diphosphate:farnesyl-diphosphate farnesyltransferase, EC 2.5.1.21). Squalene Synthase catalyzes the formation of Squalene from trans-farnesyl diphosphate in two distinct steps and is the first committed enzyme for the biosynthesis of cholesterol. Recently, a truncated form of the enzyme from rat hepatocytes was purified, and monospecific antibodies for Squalene Synthase were produced. This enabled the subcellular localization of Squalene Synthase by three different methods: (i) analytical subcellular fractionation and measurements of enzyme activities; (ii) immunodeterminations of Squalene Synthase in the isolated subcellular fractions with a monospecific antibody; and (iii) immunoelectron microscopy. All three methods gave consistent results. The data clearly illustrate that Squalene Synthase enzymatic activity and Squalene Synthase are exclusively localized in the endoplasmic reticulum. In rat hepatic peroxisomes we were not able to detect any Squalene Synthase. In addition, we also demonstrated that Squalene Synthase in the microsomal fraction is dramatically regulated by a number of hypolipidemic drugs and dietary treatments.

Y Fukuma - One of the best experts on this subject based on the ideXlab platform.

  • Role of Squalene Synthase in prostate cancer risk and the biological aggressiveness of human prostate cancer
    Prostate Cancer and Prostatic Diseases, 2012
    Co-Authors: Y Fukuma, H Matsui, H Koike, Y Sekine, I Shechter, N Ohtake, S Nakata, K Suzuki
    Abstract:

    Background: We previously conducted a genome-wide linkage analysis of Japanese nuclear families affected with prostate cancer and showed that the susceptibility to prostate cancer was closely linked to D8S550 at 8p23. The role of farnesyl diphosphate farnesyltransferase ( FDFT1 ), which is located under the peak marker D8S550 at 8p23, and Squalene Synthase, the enzyme encoded by FDFT1 , in prostate cancer was studied. Methods: The association among common variants of FDFT1 with prostate cancer risk, the promoter activities of FDFT1 with different genotypes and the effects of inhibition of Squalene Synthase were studied, and the FDFT1 transcript levels of human prostate samples were quantified. Results: The A allele of rs2645429 was significantly associated with prostate cancer risk in a Japanese familial prostate cancer population. Rs2645429 was located in the promoter region of FDFT1 , and the AA genotype showed significantly increased promoter activity. The knockdown of FDFT1 mRNA expression or Squalene Synthase inhibition led to a significant decrease in prostate cancer cell proliferation. Additionally, human prostate cancer specimens expressed significantly higher levels of FDFT1 mRNA compared with noncancerous specimens. Finally, aggressive cancers showed higher transcript levels. Conclusions: FDFT1 and its encoded enzyme, Squalene Synthase, may play an important role in prostate cancer development and its aggressive phenotypes.

  • Role of Squalene Synthase in prostate cancer risk and the biological aggressiveness of human prostate cancer.
    Prostate cancer and prostatic diseases, 2012
    Co-Authors: Y Fukuma, H Matsui, H Koike, Y Sekine, I Shechter, N Ohtake, S Nakata, Kazuto Ito, K Suzuki
    Abstract:

    Role of Squalene Synthase in prostate cancer risk and the biological aggressiveness of human prostate cancer

I Shechter - One of the best experts on this subject based on the ideXlab platform.

  • Role of Squalene Synthase in prostate cancer risk and the biological aggressiveness of human prostate cancer
    Prostate Cancer and Prostatic Diseases, 2012
    Co-Authors: Y Fukuma, H Matsui, H Koike, Y Sekine, I Shechter, N Ohtake, S Nakata, K Suzuki
    Abstract:

    Background: We previously conducted a genome-wide linkage analysis of Japanese nuclear families affected with prostate cancer and showed that the susceptibility to prostate cancer was closely linked to D8S550 at 8p23. The role of farnesyl diphosphate farnesyltransferase ( FDFT1 ), which is located under the peak marker D8S550 at 8p23, and Squalene Synthase, the enzyme encoded by FDFT1 , in prostate cancer was studied. Methods: The association among common variants of FDFT1 with prostate cancer risk, the promoter activities of FDFT1 with different genotypes and the effects of inhibition of Squalene Synthase were studied, and the FDFT1 transcript levels of human prostate samples were quantified. Results: The A allele of rs2645429 was significantly associated with prostate cancer risk in a Japanese familial prostate cancer population. Rs2645429 was located in the promoter region of FDFT1 , and the AA genotype showed significantly increased promoter activity. The knockdown of FDFT1 mRNA expression or Squalene Synthase inhibition led to a significant decrease in prostate cancer cell proliferation. Additionally, human prostate cancer specimens expressed significantly higher levels of FDFT1 mRNA compared with noncancerous specimens. Finally, aggressive cancers showed higher transcript levels. Conclusions: FDFT1 and its encoded enzyme, Squalene Synthase, may play an important role in prostate cancer development and its aggressive phenotypes.

  • Role of Squalene Synthase in prostate cancer risk and the biological aggressiveness of human prostate cancer.
    Prostate cancer and prostatic diseases, 2012
    Co-Authors: Y Fukuma, H Matsui, H Koike, Y Sekine, I Shechter, N Ohtake, S Nakata, Kazuto Ito, K Suzuki
    Abstract:

    Role of Squalene Synthase in prostate cancer risk and the biological aggressiveness of human prostate cancer

  • Localization of the Squalene Synthase gene (FDFT1) to human chromosome 8p22-p23. 1
    Genomics, 1994
    Co-Authors: I Shechter, Deanna G. Conrad, Iris Hart, Ralph Berger, Timothy L. Mckenzie, John Bleskan, David Patterson
    Abstract:

    Recently, we reported the isolation of a cDNA encoding the human enzyme Squalene Synthase, the first step of sterol biosynthesis uniquely committed to synthesis of cholesterol (6). As such, it is likely that this enzyme occupies a critical regulatory position in the synthesis of cholesterol. As part of continuing studies of the role of this gene in cellular metabolism, we undertook the mapping of this gene on the human chromosomes. To localize the gene, we have first isolated a yeast artificial chromosome (YAC) containing the Squalene Synthase gene. We then used fluorescence in situ hybridization (FISH) with yeast DNA containing the YAC to localize the gene to chromosome 8. Assignment to human chromosome 8 was confirmed by polymerase chain reaction analysis of a somatic cell hybrid containing human chromosome 8. Use of a somatic cell hybrid regional mapping panel dividing chromosome 8 into several fragments localized the gene to 8p21-pter. Fractional length analysis of the FISH mapping placed the signal generated with this YAC at 8p22-p23.1.

H Koike - One of the best experts on this subject based on the ideXlab platform.

  • Role of Squalene Synthase in prostate cancer risk and the biological aggressiveness of human prostate cancer
    Prostate Cancer and Prostatic Diseases, 2012
    Co-Authors: Y Fukuma, H Matsui, H Koike, Y Sekine, I Shechter, N Ohtake, S Nakata, K Suzuki
    Abstract:

    Background: We previously conducted a genome-wide linkage analysis of Japanese nuclear families affected with prostate cancer and showed that the susceptibility to prostate cancer was closely linked to D8S550 at 8p23. The role of farnesyl diphosphate farnesyltransferase ( FDFT1 ), which is located under the peak marker D8S550 at 8p23, and Squalene Synthase, the enzyme encoded by FDFT1 , in prostate cancer was studied. Methods: The association among common variants of FDFT1 with prostate cancer risk, the promoter activities of FDFT1 with different genotypes and the effects of inhibition of Squalene Synthase were studied, and the FDFT1 transcript levels of human prostate samples were quantified. Results: The A allele of rs2645429 was significantly associated with prostate cancer risk in a Japanese familial prostate cancer population. Rs2645429 was located in the promoter region of FDFT1 , and the AA genotype showed significantly increased promoter activity. The knockdown of FDFT1 mRNA expression or Squalene Synthase inhibition led to a significant decrease in prostate cancer cell proliferation. Additionally, human prostate cancer specimens expressed significantly higher levels of FDFT1 mRNA compared with noncancerous specimens. Finally, aggressive cancers showed higher transcript levels. Conclusions: FDFT1 and its encoded enzyme, Squalene Synthase, may play an important role in prostate cancer development and its aggressive phenotypes.

  • Role of Squalene Synthase in prostate cancer risk and the biological aggressiveness of human prostate cancer.
    Prostate cancer and prostatic diseases, 2012
    Co-Authors: Y Fukuma, H Matsui, H Koike, Y Sekine, I Shechter, N Ohtake, S Nakata, Kazuto Ito, K Suzuki
    Abstract:

    Role of Squalene Synthase in prostate cancer risk and the biological aggressiveness of human prostate cancer