The Experts below are selected from a list of 993 Experts worldwide ranked by ideXlab platform
Russell A Deboseboyd - One of the best experts on this subject based on the ideXlab platform.
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synergistic impact of d δ tocotrienol and Geranylgeraniol on the growth and hmg coa reductase of human du145 prostate carcinoma cells
Nutrition and Cancer, 2017Co-Authors: Hoda Yeganehjoo, Russell A Deboseboyd, Brian K McfarlinAbstract:The growth-suppressive effect of d-δ-tocotrienol and Geranylgeraniol is at least partially attributed to their impact on 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme in the mevalonate pathway that provides essential intermediates for the posttranslational modification of growth-related proteins including RAS. We hypothesize that these agents synergistically impact cell growth based on their complementary mechanisms of action with HMG CoA reductase. d-δ-tocotrienol (0-40 µmol/L; half maximal inhibitory concentration [IC50] = 15 µmol/L) and Geranylgeraniol (0-100 µmol/L; IC50 = 60 µmol/L) each induced concentration-dependent suppression of the growth of human DU145 prostate carcinoma cells. Blends of the two agents synergistically suppressed the growth of DU145 cells, with combination index values ranging 0.67-0.75. While 7.5 µmol/L d-δ-tocotrienol and 30 µmol/L Geranylgeraniol individually had no impact on cell cycle distribution in DU145 cells, a blend of the agents induced cell cycle arrest at the G1 phase. The synergistic downregulation of the expression of HMG CoA reductase by 7.5 µmol/L d-δ-tocotrienol and 30 µmol/L Geranylgeraniol was accompanied by a reduction in membrane K-RAS protein. Our finding supports the cancer chemopreventive action of plant-based diets and their isoprenoid constituents. Properly formulated isoprenoids and derivatives may provide novel approaches in prostate cancer prevention and therapy.
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the prenyltransferase ubiad1 is the target of Geranylgeraniol in degradation of hmg coa reductase
eLife, 2015Co-Authors: Marc M Schumacher, Joachim Seemann, Rania Elsabrouty, Russell A DeboseboydAbstract:Schnyder corneal dystrophy (SCD) is an autosomal dominant disorder in humans characterized by abnormal accumulation of cholesterol in the cornea. SCD-associated mutations have been identified in the gene encoding UBIAD1, a prenyltransferase that synthesizes vitamin K2. Here, we show that sterols stimulate binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase, which is subject to sterol-accelerated, endoplasmic reticulum (ER)-associated degradation augmented by the nonsterol isoprenoid Geranylgeraniol through an unknown mechanism. Geranylgeraniol inhibits binding of UBIAD1 to reductase, allowing its degradation and promoting transport of UBIAD1 from the ER to the Golgi. CRISPR-CAS9-mediated knockout of UBIAD1 relieves the Geranylgeraniol requirement for reductase degradation. SCD-associated mutations in UBIAD1 block its displacement from reductase in the presence of Geranylgeraniol, thereby preventing degradation of reductase. The current results identify UBIAD1 as the elusive target of Geranylgeraniol in reductase degradation, the inhibition of which may contribute to accumulation of cholesterol in SCD.
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sequential actions of the aaa atpase valosin containing protein vcp p97 and the proteasome 19 s regulatory particle in sterol accelerated endoplasmic reticulum er associated degradation of 3 hydroxy 3 methylglutaryl coenzyme a reductase
Journal of Biological Chemistry, 2014Co-Authors: Lindsey L Morris, Isamu Z Hartman, Joachim Seemann, Russell A DeboseboydAbstract:Accelerated endoplasmic reticulum (ER)-associated degradation (ERAD) of the cholesterol biosynthetic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase results from its sterol-induced binding to ER membrane proteins called Insig-1 and Insig-2. This binding allows for subsequent ubiquitination of reductase by Insig-associated ubiquitin ligases. Once ubiquitinated, reductase becomes dislocated from ER membranes into the cytosol for degradation by 26 S proteasomes through poorly defined reactions mediated by the AAA-ATPase valosin-containing protein (VCP)/p97 and augmented by the nonsterol isoprenoid Geranylgeraniol. Here, we report that the oxysterol 25-hydroxycholesterol and Geranylgeraniol combine to trigger extraction of reductase across ER membranes prior to its cytosolic release. This conclusion was drawn from studies utilizing a novel assay that measures membrane extraction of reductase by determining susceptibility of a lumenal epitope in the enzyme to in vitro protease digestion. Susceptibility of the lumenal epitope to protease digestion and thus membrane extraction of reductase were tightly regulated by 25-hydroxycholesterol and Geranylgeraniol. The reaction was inhibited by RNA interference-mediated knockdown of either Insigs or VCP/p97. In contrast, reductase continued to become membrane-extracted, but not cytosolically dislocated, in cells deficient for AAA-ATPases of the proteasome 19 S regulatory particle. These findings establish sequential roles for VCP/p97 and the 19 S regulatory particle in the sterol-accelerated ERAD of reductase that may be applicable to the ERAD of other substrates.
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Geranylgeraniol suppresses the viability of human du145 prostate carcinoma cells and the level of hmg coa reductase
Experimental Biology and Medicine, 2013Co-Authors: Nicolle V Fernandes, Lindsey L Morris, Russell A Deboseboyd, Rajasekhar Katuru, Hoda Yeganehjoo, Renee MichonAbstract:The rate-limiting enzyme of the mevalonate pathway, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, provides essential intermediates for the prenylation of nuclear lamins and Ras and dolichol-mediated glycosylation of growth factor receptors. The diterpene Geranylgeraniol downregulates the level of HMG CoA reductase and suppresses the growth of human liver, lung, ovary, pancreas, colon, stomach, and blood tumors. We evaluated the growth-suppressive activity of Geranylgeraniol in human prostate carcinoma cells. Geranylgeraniol induced dose-dependent suppression of the viability of human DU145 prostate carcinoma cells (IC50=80±18 µmol/L, n=5) following 72-h incubations in 96-well plates. Cell cycle was arrested at the G1 phase with a concomitant decrease in cyclin D1 protein. Geranylgeraniol-induced apoptosis was detected by flow cytometric analysis, fluorescence microscopy following acridine orange and ethidium bromide dual staining, and caspase-3 activation. Geranylgeraniol-induced viability suppression was accompanied by concentration-dependent decrease in the level of HMG CoA reductase protein. As a nonsterol molecule that downregulates HMG CoA reductase in the presence of sterols, Geranylgeraniol may have potential in the chemoprevention and/or therapy of human prostate cancer.
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insig dependent ubiquitination and degradation of mammalian 3 hydroxy 3 methylglutaryl coa reductase stimulated by sterols and Geranylgeraniol
Journal of Biological Chemistry, 2003Co-Authors: Navdar Sever, Baoliang Song, Daisuke Yabe, Joseph L Goldstein, Michael S Brown, Russell A DeboseboydAbstract:The endoplasmic reticulum enzyme 3-hydroxy-3-methylglutaryl-CoA reductase produces mevalonate, which is converted to sterols and to other products, including Geranylgeraniol groups attached to proteins. The enzyme is known to be ubiquitinated and rapidly degraded when sterols and nonsterol end products of mevalonate metabolism accumulate in cells. Here, we use RNA interference to show that sterol-accelerated ubiquitination of reductase requires Insig-1 and Insig-2, membrane-bound proteins of the endoplasmic reticulum that were shown previously to accelerate degradation of reductase when overexpressed by transfection. Alanine substitution experiments reveal that binding of reductase to Insigs and subsequent ubiquitination require the tetrapeptide sequence YIYF in the second membrane-spanning helix of reductase. The YIYF peptide is also found in the sterol-sensing domain of SCAP, another protein that binds to Insigs in a sterolstimulated fashion. When lysine 248 of reductase is substituted with arginine, Insig binding persists, but the reductase is no longer ubiquitinated and degradation is markedly slowed. Lysine 248 is predicted to lie immediately adjacent to a membrane-spanning helix, suggesting that a membrane-bound ubiquitin transferase is responsible. Finally, we show that Insig-dependent, sterolstimulated degradation of reductase is further accelerated when cells are also supplied with the 20carbon isoprenoid Geranylgeraniol, but not the 15carbon farnesol, raising the possibility that the nonsterol potentiator of reductase regulation is a geranylgeranylated protein.
Chenyang Jiang - One of the best experts on this subject based on the ideXlab platform.
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alendronate prevents angiotensin ii induced collagen i production through geranylgeranylation dependent rhoa rho kinase activation in cardiac fibroblasts
Journal of Pharmacological Sciences, 2015Co-Authors: Meihui Wang, Jun Zhu, Shiquan Chen, Chenyang JiangAbstract:Collagen I is the main component of extracellular matrix in cardiac fibrosis. Our previous studies have reported inhibition of farnesylpyrophosphate synthase prevents angiotensin II-induced cardiac fibrosis, while the exact molecular mechanism was still unclear. This paper was designed to investigate the effect of alendronate, a farnesylpyrophosphate synthase inhibitor, on regulating angiotensin II-induced collagen I expression in cultured cardiac fibroblasts and to explore the underlying mechanism. By measuring the mRNA and protein levels of collagen I, we found that alendronate prevented angiotensin II-induced collagen I production in a dose-dependent manner. The inhibitory effect on collagen I expression was reversed by Geranylgeraniol, and mimicked by inhibitors of RhoA/Rho kinase pathway including C3 exoenzyme and GGTI-286. Thus we suggested geranylgeranylation-dependent RhoA/Rho kinase activation was involved in alendronate-mediated anti-collagen I synthetic effect. Furthermore, we accessed the activation status of RhoA in alendronate-, Geranylgeraniol- and GGTI-286-treated cardiac fibroblasts and gave an indirect evidence for RhoA activation via geranylgeranylation. Then we came to the conclusion that in cardiac fibroblasts, alendronate could protect against angiotensin II-induced collagen I synthesis through inhibition of geranylgeranylation and inactivation of RhoA/Rho kinase signaling. Targeting geranylgeranylation and RhoA/Rho kinase signaling will hopefully serve as therapeutic strategies to reduce fibrosis in heart remodeling.
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Alendronate prevents angiotensin II-induced collagen I production through geranylgeranylation-dependent RhoA/Rho kinase activation in cardiac fibroblasts
Elsevier, 2015Co-Authors: Meihui Wang, Jun Zhu, Shiquan Chen, Chenyang JiangAbstract:Collagen I is the main component of extracellular matrix in cardiac fibrosis. Our previous studies have reported inhibition of farnesylpyrophosphate synthase prevents angiotensin II-induced cardiac fibrosis, while the exact molecular mechanism was still unclear. This paper was designed to investigate the effect of alendronate, a farnesylpyrophosphate synthase inhibitor, on regulating angiotensin II-induced collagen I expression in cultured cardiac fibroblasts and to explore the underlying mechanism. By measuring the mRNA and protein levels of collagen I, we found that alendronate prevented angiotensin II-induced collagen I production in a dose-dependent manner. The inhibitory effect on collagen I expression was reversed by Geranylgeraniol, and mimicked by inhibitors of RhoA/Rho kinase pathway including C3 exoenzyme and GGTI-286. Thus we suggested geranylgeranylation-dependent RhoA/Rho kinase activation was involved in alendronate-mediated anti-collagen I synthetic effect. Furthermore, we accessed the activation status of RhoA in alendronate-, Geranylgeraniol- and GGTI-286-treated cardiac fibroblasts and gave an indirect evidence for RhoA activation via geranylgeranylation. Then we came to the conclusion that in cardiac fibroblasts, alendronate could protect against angiotensin II-induced collagen I synthesis through inhibition of geranylgeranylation and inactivation of RhoA/Rho kinase signaling. Targeting geranylgeranylation and RhoA/Rho kinase signaling will hopefully serve as therapeutic strategies to reduce fibrosis in heart remodeling
Hoda Yeganehjoo - One of the best experts on this subject based on the ideXlab platform.
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synergistic impact of d δ tocotrienol and Geranylgeraniol on the growth and hmg coa reductase of human du145 prostate carcinoma cells
Nutrition and Cancer, 2017Co-Authors: Hoda Yeganehjoo, Russell A Deboseboyd, Brian K McfarlinAbstract:The growth-suppressive effect of d-δ-tocotrienol and Geranylgeraniol is at least partially attributed to their impact on 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme in the mevalonate pathway that provides essential intermediates for the posttranslational modification of growth-related proteins including RAS. We hypothesize that these agents synergistically impact cell growth based on their complementary mechanisms of action with HMG CoA reductase. d-δ-tocotrienol (0-40 µmol/L; half maximal inhibitory concentration [IC50] = 15 µmol/L) and Geranylgeraniol (0-100 µmol/L; IC50 = 60 µmol/L) each induced concentration-dependent suppression of the growth of human DU145 prostate carcinoma cells. Blends of the two agents synergistically suppressed the growth of DU145 cells, with combination index values ranging 0.67-0.75. While 7.5 µmol/L d-δ-tocotrienol and 30 µmol/L Geranylgeraniol individually had no impact on cell cycle distribution in DU145 cells, a blend of the agents induced cell cycle arrest at the G1 phase. The synergistic downregulation of the expression of HMG CoA reductase by 7.5 µmol/L d-δ-tocotrienol and 30 µmol/L Geranylgeraniol was accompanied by a reduction in membrane K-RAS protein. Our finding supports the cancer chemopreventive action of plant-based diets and their isoprenoid constituents. Properly formulated isoprenoids and derivatives may provide novel approaches in prostate cancer prevention and therapy.
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Original Research Featured Article Geranylgeraniol suppresses the viability of human DU145 prostate carcinoma cells and the level of HMG CoA reductase
2016Co-Authors: Nicolle V Fern, Lindsey L Morris, Rajasekhar Katuru, Hoda Yeganehjoo, Russell A Debose-boyd, Renee MichonAbstract:The rate-limiting enzyme of the mevalonate pathway, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, provides essential intermediates for the prenylation of nuclear lamins and Ras and dolichol-mediated glycosylation of growth factor recep-tors. The diterpene Geranylgeraniol downregulates the level of HMG CoA reductase and suppresses the growth of human liver, lung, ovary, pancreas, colon, stomach, and blood tumors. We evaluated the growth-suppressive activity of Geranylgeraniol in human prostate carcinoma cells. Geranylgeraniol induced dose-dependent suppression of the viability of human DU145 prostate carcinoma cells (IC50 80 18 mmol/L, n 5) following 72-h incubations in 96-well plates. Cell cycle was arrested at the G1 phase with a concomitant decrease in cyclin D1 protein. Geranylgeraniol-induced apoptosis was detected by flow cytometric analysis, fluorescence microscopy following acridine orange and ethidium bromide dual staining, and caspase-3 activation. Geranylgeraniol-induced viability suppression was accompanied by concentration-dependent decrease in the level of HMG CoA reductase protein. As a nonsterol molecule that downregulates HMG CoA reductase in the presence of sterols, geranylger-aniol may have potential in the chemoprevention and/or therapy of human prostate cancer
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Geranylgeraniol suppresses the viability of human du145 prostate carcinoma cells and the level of hmg coa reductase
Experimental Biology and Medicine, 2013Co-Authors: Nicolle V Fernandes, Lindsey L Morris, Russell A Deboseboyd, Rajasekhar Katuru, Hoda Yeganehjoo, Renee MichonAbstract:The rate-limiting enzyme of the mevalonate pathway, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, provides essential intermediates for the prenylation of nuclear lamins and Ras and dolichol-mediated glycosylation of growth factor receptors. The diterpene Geranylgeraniol downregulates the level of HMG CoA reductase and suppresses the growth of human liver, lung, ovary, pancreas, colon, stomach, and blood tumors. We evaluated the growth-suppressive activity of Geranylgeraniol in human prostate carcinoma cells. Geranylgeraniol induced dose-dependent suppression of the viability of human DU145 prostate carcinoma cells (IC50=80±18 µmol/L, n=5) following 72-h incubations in 96-well plates. Cell cycle was arrested at the G1 phase with a concomitant decrease in cyclin D1 protein. Geranylgeraniol-induced apoptosis was detected by flow cytometric analysis, fluorescence microscopy following acridine orange and ethidium bromide dual staining, and caspase-3 activation. Geranylgeraniol-induced viability suppression was accompanied by concentration-dependent decrease in the level of HMG CoA reductase protein. As a nonsterol molecule that downregulates HMG CoA reductase in the presence of sterols, Geranylgeraniol may have potential in the chemoprevention and/or therapy of human prostate cancer.
Meihui Wang - One of the best experts on this subject based on the ideXlab platform.
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alendronate prevents angiotensin ii induced collagen i production through geranylgeranylation dependent rhoa rho kinase activation in cardiac fibroblasts
Journal of Pharmacological Sciences, 2015Co-Authors: Meihui Wang, Jun Zhu, Shiquan Chen, Chenyang JiangAbstract:Collagen I is the main component of extracellular matrix in cardiac fibrosis. Our previous studies have reported inhibition of farnesylpyrophosphate synthase prevents angiotensin II-induced cardiac fibrosis, while the exact molecular mechanism was still unclear. This paper was designed to investigate the effect of alendronate, a farnesylpyrophosphate synthase inhibitor, on regulating angiotensin II-induced collagen I expression in cultured cardiac fibroblasts and to explore the underlying mechanism. By measuring the mRNA and protein levels of collagen I, we found that alendronate prevented angiotensin II-induced collagen I production in a dose-dependent manner. The inhibitory effect on collagen I expression was reversed by Geranylgeraniol, and mimicked by inhibitors of RhoA/Rho kinase pathway including C3 exoenzyme and GGTI-286. Thus we suggested geranylgeranylation-dependent RhoA/Rho kinase activation was involved in alendronate-mediated anti-collagen I synthetic effect. Furthermore, we accessed the activation status of RhoA in alendronate-, Geranylgeraniol- and GGTI-286-treated cardiac fibroblasts and gave an indirect evidence for RhoA activation via geranylgeranylation. Then we came to the conclusion that in cardiac fibroblasts, alendronate could protect against angiotensin II-induced collagen I synthesis through inhibition of geranylgeranylation and inactivation of RhoA/Rho kinase signaling. Targeting geranylgeranylation and RhoA/Rho kinase signaling will hopefully serve as therapeutic strategies to reduce fibrosis in heart remodeling.
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Alendronate prevents angiotensin II-induced collagen I production through geranylgeranylation-dependent RhoA/Rho kinase activation in cardiac fibroblasts
Elsevier, 2015Co-Authors: Meihui Wang, Jun Zhu, Shiquan Chen, Chenyang JiangAbstract:Collagen I is the main component of extracellular matrix in cardiac fibrosis. Our previous studies have reported inhibition of farnesylpyrophosphate synthase prevents angiotensin II-induced cardiac fibrosis, while the exact molecular mechanism was still unclear. This paper was designed to investigate the effect of alendronate, a farnesylpyrophosphate synthase inhibitor, on regulating angiotensin II-induced collagen I expression in cultured cardiac fibroblasts and to explore the underlying mechanism. By measuring the mRNA and protein levels of collagen I, we found that alendronate prevented angiotensin II-induced collagen I production in a dose-dependent manner. The inhibitory effect on collagen I expression was reversed by Geranylgeraniol, and mimicked by inhibitors of RhoA/Rho kinase pathway including C3 exoenzyme and GGTI-286. Thus we suggested geranylgeranylation-dependent RhoA/Rho kinase activation was involved in alendronate-mediated anti-collagen I synthetic effect. Furthermore, we accessed the activation status of RhoA in alendronate-, Geranylgeraniol- and GGTI-286-treated cardiac fibroblasts and gave an indirect evidence for RhoA activation via geranylgeranylation. Then we came to the conclusion that in cardiac fibroblasts, alendronate could protect against angiotensin II-induced collagen I synthesis through inhibition of geranylgeranylation and inactivation of RhoA/Rho kinase signaling. Targeting geranylgeranylation and RhoA/Rho kinase signaling will hopefully serve as therapeutic strategies to reduce fibrosis in heart remodeling
Renee Michon - One of the best experts on this subject based on the ideXlab platform.
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Original Research Featured Article Geranylgeraniol suppresses the viability of human DU145 prostate carcinoma cells and the level of HMG CoA reductase
2016Co-Authors: Nicolle V Fern, Lindsey L Morris, Rajasekhar Katuru, Hoda Yeganehjoo, Russell A Debose-boyd, Renee MichonAbstract:The rate-limiting enzyme of the mevalonate pathway, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, provides essential intermediates for the prenylation of nuclear lamins and Ras and dolichol-mediated glycosylation of growth factor recep-tors. The diterpene Geranylgeraniol downregulates the level of HMG CoA reductase and suppresses the growth of human liver, lung, ovary, pancreas, colon, stomach, and blood tumors. We evaluated the growth-suppressive activity of Geranylgeraniol in human prostate carcinoma cells. Geranylgeraniol induced dose-dependent suppression of the viability of human DU145 prostate carcinoma cells (IC50 80 18 mmol/L, n 5) following 72-h incubations in 96-well plates. Cell cycle was arrested at the G1 phase with a concomitant decrease in cyclin D1 protein. Geranylgeraniol-induced apoptosis was detected by flow cytometric analysis, fluorescence microscopy following acridine orange and ethidium bromide dual staining, and caspase-3 activation. Geranylgeraniol-induced viability suppression was accompanied by concentration-dependent decrease in the level of HMG CoA reductase protein. As a nonsterol molecule that downregulates HMG CoA reductase in the presence of sterols, geranylger-aniol may have potential in the chemoprevention and/or therapy of human prostate cancer
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Geranylgeraniol suppresses the viability of human du145 prostate carcinoma cells and the level of hmg coa reductase
Experimental Biology and Medicine, 2013Co-Authors: Nicolle V Fernandes, Lindsey L Morris, Russell A Deboseboyd, Rajasekhar Katuru, Hoda Yeganehjoo, Renee MichonAbstract:The rate-limiting enzyme of the mevalonate pathway, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, provides essential intermediates for the prenylation of nuclear lamins and Ras and dolichol-mediated glycosylation of growth factor receptors. The diterpene Geranylgeraniol downregulates the level of HMG CoA reductase and suppresses the growth of human liver, lung, ovary, pancreas, colon, stomach, and blood tumors. We evaluated the growth-suppressive activity of Geranylgeraniol in human prostate carcinoma cells. Geranylgeraniol induced dose-dependent suppression of the viability of human DU145 prostate carcinoma cells (IC50=80±18 µmol/L, n=5) following 72-h incubations in 96-well plates. Cell cycle was arrested at the G1 phase with a concomitant decrease in cyclin D1 protein. Geranylgeraniol-induced apoptosis was detected by flow cytometric analysis, fluorescence microscopy following acridine orange and ethidium bromide dual staining, and caspase-3 activation. Geranylgeraniol-induced viability suppression was accompanied by concentration-dependent decrease in the level of HMG CoA reductase protein. As a nonsterol molecule that downregulates HMG CoA reductase in the presence of sterols, Geranylgeraniol may have potential in the chemoprevention and/or therapy of human prostate cancer.