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https://www.readbyqxmd.com/read/27802439/metabolic-stress-induces-caspase-3-mediated-degradation-and-inactivation-of-farnesyl-and-geranylgeranyl-transferase-activities-in-pancreatic-%C3%AE-cells
#1
Rajakrishnan Veluthakal, Daleep K Arora, Marc L Goalstone, Renu A Kowluru, Anjaneyulu Kowluru
BACKGROUND/AIMS: At least 300 prenylated proteins are identified in the human genome; the majority of which partake in a variety of cellular processes including growth, differentiation, cytoskeletal organization/dynamics and vesicle trafficking. Aberrant prenylation of proteins is implicated in human pathologies including cancer; neurodegenerative diseases, retinitis pigmentosa, and premature ageing syndromes. Original observations from our laboratory have demonstrated that prenylation of proteins [small G-proteins and γ-subunits of trimeric G-proteins] is requisite for physiological insulin secretion...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27620969/pyrazole-based-potent-inhibitors-of-ggt1-synthesis-biological-evaluation-and-molecular-docking-studies
#2
Muhammad Mansha, Udayappan Udhaya Kumari, Zoe Cournia, Nisar Ullah
In this study, a series of pyrazole-based structural analogues of GGTI-DU40 (1) have been synthesized and biologically evaluated for geranylgeranyltransferase 1 (GGT1) and farnesyltransferase (FT) inhibition. The screening results revealed that 2 (IC50 = 2.4 μM) and 5 (IC50 = 3.1 μM) are potent GGT1 inhibitors (GGTIs), possessing higher inhibitory activity compared to the control compound 1 (IC50 = 3.3 μM). The anti-proliferative efficacy of these compounds was further assayed against MDA-MB-231 cells which indicated a significantly higher activity of 2 (IC50 = 7...
September 3, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27545498/cross-talk-between-autophagy-and-klf2-determines-endothelial-cell-phenotype-and-microvascular-function-in-acute-liver-injury
#3
Sergi Guixé-Muntet, Fernanda Cristina de Mesquita, Sergi Vila, Virginia Hernández-Gea, Carmen Peralta, Juan Carlos García-Pagán, Jaime Bosch, Jordi Gracia-Sancho
BACKGROUND & AIMS: The transcription factor Krüppel-like factor 2 (KLF2), inducible by simvastatin, confers endothelial vasoprotection. Considering recent data suggesting activation of autophagy by statins, we aimed to: 1) characterize the relationship between autophagy and KLF2 in the endothelium, 2) assess this relationship in acute liver injury (cold ischemia/reperfusion) and 3) study the effects of modulating KLF2-autophagy in vitro and in vivo. METHODS: Autophagic flux, the vasoprotective KLF2 pathway, cell viability and microvascular function were assessed in endothelial cells and in various pre-clinical models of acute liver injury (cold storage and warm reperfusion)...
August 18, 2016: Journal of Hepatology
https://www.readbyqxmd.com/read/26924327/effect-of-hmg-coa-reductase-inhibition-on-vascular-smooth-muscle-cells-extracellular-matrix-production-role-of-rhoa
#4
Rogelio Palomino-Morales, Sonia Perales, Carolina Torres, Ana Linares, Maria J Alejandre
Cholesterol-lowering effects apart, statins can improve the endothelial function, stabilize the atherosclerotic plaques, decrease the oxidative stress and inflammation and inhibit the thrombogenic response by means of the inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules. We aimed to evaluate whether the effect of statins on RhoA activity mediate extracellular matrix production, particularly affecting collagen type I, in smooth muscle cells (SMCs). Our results showed that lovastatin decreased collagen expression in primary cultured chicken SMCs as determined by incorporation of [H3]-proline, RT-PCR and immunocytochemistry...
2016: Current Vascular Pharmacology
https://www.readbyqxmd.com/read/26908642/statins-inhibit-blastocyst-formation-by-preventing-geranylgeranylation
#5
Vernadeth B Alarcon, Yusuke Marikawa
STUDY HYPOTHESIS: Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase of the mevalonate pathway and prescription drugs that treat hypercholesterolemia, compromise preimplantation mouse development via modulation of HIPPO signaling. STUDY FINDING: HMG-CoA reductase activity is required for trophectoderm specification, namely blastocyst cavity formation and Yes-associated protein (YAP) nuclear localization, through the production of isoprenoid geranylgeranyl pyrophosphate (GGPP) and the action of geranylgeranyl transferase...
May 2016: Molecular Human Reproduction
https://www.readbyqxmd.com/read/26690896/astrocyte-ggti-mediated-rac1-prenylation-upregulates-nf-%C3%AE%C2%BAb-expression-and-promotes-neuronal-apoptosis-following-hypoxia-ischemia
#6
Shangfeng Gao, Jianbing Mo, Long Chen, Yan Wang, Xueqiang Mao, Yi Shi, Xianfeng Zhang, Rutong Yu, Xiuping Zhou
Stroke is the fifth leading cause of death for Americans, and about 87% of all strokes are ischemic strokes. Astrogliosis plays a crucial role in the pathophysiology of delayed neuronal death (DND) following ischemic stroke. Here we reported that astrocyte geranylgeranyltransferase I (GGTI)-mediated Rac1 activation up-regulated NF-κB expression and promoted the neuronal apoptosis after oxygen-glucose deprivation followed by oxygen-glucose regeneration (OGD/R). We found that GGTIβ (a specific subunit of GGTI) and NF-κB-p65 levels as determined by Western blot and/or immunofluorescent analysis were significantly up-regulated in the reactive astrocytes both in rat transient middle cerebral artery occlusion (tMCAO) and in cell OGD/R models...
April 2016: Neuropharmacology
https://www.readbyqxmd.com/read/26648485/protein-geranylgeranyltransferase-type-1-as-a-target-in-cancer
#7
REVIEW
Nisar Ullah, Muhammad Mansha, Patrick J Casey
The process of protein prenylation involves the covalent linkage of either farnesyl (15-carbon) or geranylgeranyl (20-carbon) isoprenoid lipds to conserved cysteine residues in the carboxyl-terminus of proteins. Protein geranylgeranyltransferase I (GGTase-I) is the enzyme that catalyzes the addition of the geranylgeranyl moiety from geranylgeranyl pyrophosphate to the target protein, which contains a Cterminal consensus sequence termed a CaaX motif. Geranylgeranylation is important to the function of a number of proteins, including the majority of Rho GTPases, G protein gamma subunits, and several other regulatory proteins...
2016: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/26627555/alendronate-prevents-angiotensin-ii-induced-collagen-i-production-through-geranylgeranylation-dependent-rhoa-rho-kinase-activation-in-cardiac-fibroblasts
#8
Yang Ye, Xue Lv, Mei-hui Wang, Jun Zhu, Shi-quan Chen, Chen-yang Jiang, Guo-sheng Fu
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...
December 2015: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/26352258/nanoformulation-of-geranylgeranyltransferase-i-inhibitors-for-cancer-therapy-liposomal-encapsulation-and-ph-dependent-delivery-to-cancer-cells
#9
Jie Lu, Kohei Yoshimura, Koichi Goto, Craig Lee, Ken Hamura, Ohyun Kwon, Fuyuhiko Tamanoi
Small molecule inhibitors against protein geranylgeranyltransferase-I such as P61A6 have been shown to inhibit proliferation of a variety of human cancer cells and exhibit antitumor activity in mouse models. Development of these inhibitors could be dramatically accelerated by conferring tumor targeting and controlled release capability. As a first step towards this goal, we have encapsulated P61A6 into a new type of liposomes that open and release cargos only under low pH condition. These low pH-release type liposomes were prepared by adjusting the ratio of two types of phospholipid derivatives...
2015: PloS One
https://www.readbyqxmd.com/read/26327464/a-mouse-model-of-luciferase-transfected-stromal-cells-of-giant-cell-tumor-of-bone
#10
Carol P Y Lau, Kwok Chuen Wong, Lin Huang, Gang Li, Stephen K W Tsui, Shekhar Madhukar Kumta
A major barrier towards the study of the effects of drugs on Giant Cell Tumor of Bone (GCT) has been the lack of an animal model. In this study, we created an animal model in which GCT stromal cells survived and functioned as proliferating neoplastic cells. A proliferative cell line of GCT stromal cells was used to create a stable and luciferase-transduced cell line, Luc-G33. The cell line was characterized and was found that there were no significant differences on cell proliferation rate and recruitment of monocytes when compared with the wild type GCT stromal cells...
November 2015: Connective Tissue Research
https://www.readbyqxmd.com/read/26124569/molecular-docking-and-simulation-of-curcumin-with-geranylgeranyl-transferase1-ggtase1-and-farnesyl-transferase-ftase
#11
Parasuraman Aiya Subramani, Venkata Ramireddy Narala, R Dinakaran Michael, Dakshayani Lomada, Madhava C Reddy
Protein prenylation is a posttranslational modification that is indispensable for translocation of membrane GTPases like Ras, Rho, Ras etc. Proteins of Ras family undergo farnesylation by FTase while Rho family goes through geranylgeranylation by GGTase1. There is only an infinitesimal difference in signal recognition between FTase and GGTase1. FTase inhibitors mostly end up selecting the cells with mutated Ras proteins that have acquired affinity towards GGTase1 in cancer microcosms. Therefore, it is of interest to identify GGTase1 and FTase dual inhibitors using the docking tool AutoDock Vina...
2015: Bioinformation
https://www.readbyqxmd.com/read/25956913/significance-of-kras-pak1-crk-pathway-in-non-small-cell-lung-cancer-oncogenesis
#12
Fariborz Mortazavi, Jie Lu, Ryan Phan, Michael Lewis, Kenny Trinidad, Amir Aljilani, Gholamhossein Pezeshkpour, Fuyuhiko Tamanoi
BACKGROUND: Key effector(s) of mutated KRAS in lung cancer progression and metastasis are unknown. Here we investigated the role of PAK1/Crk axis in transduction of the oncogenic KRAS signal in non-small cell lung cancer (NSCLC). METHODS: We used NSCLC clinical specimens to examine the correlation among KRAS mutations (codon 12, 13 and 61); PAK1/Crk axis activation [p-PAK1(Thr423), p-Crk(Ser41)]; and adhesion molecules expression by immunohistochemistry. For assessing the role of proto-oncogene c-Crk as a KRAS effector, we inhibited KRAS in NSCLC cells by a combination of farnesyltransferase inhibitor (FTI) and geranylgeranyltransferase inhibitor (GGTI) and measured p-Crk-II(Ser41) by western blotting...
May 9, 2015: BMC Cancer
https://www.readbyqxmd.com/read/25882623/modulation-of-sterol-biosynthesis-regulates-viral-replication-and-cytokine-production-in-influenza-a-virus-infected-human-alveolar-epithelial-cells
#13
Kenrie P Y Hui, Denise I T Kuok, Sara S R Kang, Hung-Sing Li, Mandy M T Ng, Christine H T Bui, J S Malik Peiris, Renee W Y Chan, Michael C W Chan
Highly pathogenic H5N1 viruses continue to transmit zoonotically, with mortality higher than 60%, and pose a pandemic threat. Antivirals remain the primary choice for treating H5N1 diseases and have their limitations. Encouraging findings highlight the beneficial effects of combined treatment of host targeting agents with immune-modulatory activities. This study evaluated the undefined roles of sterol metabolic pathway in viral replication and cytokine induction by H5N1 virus in human alveolar epithelial cells...
July 2015: Antiviral Research
https://www.readbyqxmd.com/read/25881746/phagocyte-like-nadph-oxidase-nox2-promotes-activation-of-p38mapk-in-pancreatic-%C3%AE-cells-under-glucotoxic-conditions-evidence-for-a-requisite-role-of-ras-related-c3-botulinum-toxin-substrate-1-rac1
#14
Vaibhav Sidarala, Rajakrishnan Veluthakal, Khadija Syeda, Cornelis Vlaar, Philip Newsholme, Anjaneyulu Kowluru
It is well established that glucotoxicity (caused by high glucose concentrations; HG) underlies pathogenesis of islet dysfunction in diabetes. We have recently demonstrated that Nox2 plays a requisite role in the generation of reactive oxygen species (ROS) under HG conditions, resulting in mitochondrial dysregulation and loss of islet β-cell function. Herein, we investigated roles of Nox2 in the regulation of downstream stress kinase (p38MAPK) activation under HG conditions (20mM; 24h) in normal rodent islets and INS-1 832/13 cells...
June 15, 2015: Biochemical Pharmacology
https://www.readbyqxmd.com/read/25849951/atorvastatin-reduces-long-pentraxin-3-expression-in-vascular-cells-by-inhibiting-protein-geranylgeranylation
#15
Roberta Baetta, Sabrina Lento, Stefania Ghilardi, Elisa Barbati, Alberto Corsini, Elena Tremoli, Cristina Banfi
BACKGROUND: The long pentraxin PTX3 is an acute-phase multi-functional protein that might play both positive and detrimental effects under different pathophysiological conditions. We previously showed that statins down-regulate the release of PTX3 in human endothelial cells (ECs). The present study investigated the mechanism mediating this effect, its occurrence in other cells involved in atherogenesis, and whether it takes place in experimental atherosclerosis. METHODS AND RESULTS: We found that atorvastatin (1-5 μmol/L) decreased the production and release of PTX3 in human ECs through a post-transcriptional effect...
April 2015: Vascular Pharmacology
https://www.readbyqxmd.com/read/25847782/inhibition-of-farnesyl-pyrophosphate-synthase-attenuates-angiotensin-ii-induced-fibrotic-responses-in-vascular-smooth-muscle-cells
#16
Chang-Qing Du, Xiao-Wei Liu, Guang-Zhong Zeng, Hong-Feng Jin, Li-Jiang Tang
Through the regulation of the RhoA/Rho kinase (ROCK) pathway, angiotensin II (Ang II)-induced fibrotic responses contribute to vascular remodeling. Farnesyl pyrophosphate synthase (FPPS) plays an important role in cardiovascular remodeling through the modulation of the above-mentioned pathway. However, the role of FPPS in Ang II-induced fibrotic responses and the related molecular mechanisms have not yet been elucidated. In the present study, vascular smooth muscle cells (VSMCs) from Sprague-Dawley (SD) rats were stimulated with Ang II...
June 2015: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/25829196/endothelial-protective-genes-induced-by-statin-are-mimicked-by-erk5-activation-as-triggered-by-a-drug-combination-of-fti-277-and-ggti-298
#17
Uyen B Chu, Tyler Duellman, Sara J Weaver, Yunting Tao, Jay Yang
BACKGROUND: Statins are potent inhibitors of cholesterol biosynthesis and are clinically beneficial in preventing cardiovascular diseases, however, the therapeutic utility of these drugs is limited by myotoxicity. Here, we explored the mechanism of statin-mediated activation of ERK5 in the human endothelium with the goal of identifying compounds that confer endothelial protection but are nontoxic to muscle. METHODS: An ERK5-one hybrid luciferase reporter transfected into COS-7 cells with pharmacological and molecular manipulations dissected the signaling pathway leading to statin activation of ERK5...
July 2015: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/25745361/pbk-topk-mediates-geranylgeranylation-signaling-for-breast-cancer-cell-proliferation
#18
Xiaoyan Dou, Jing Wei, Aiqin Sun, Genbao Shao, Chandra Childress, Wannian Yang, Qiong Lin
PDZ binding-kinase (PBK) (also named T-lymphokine-activated killer cell-originated protein kinase (TOPK)), a serine/threonine kinase, is tightly controlled in normal tissues but elevated in many tumors, and functions in tumorigenesis and metastasis. However, the signaling that regulates expression of PBK in cancer cells remains elusive. Here we show that atorvastatin (Lipitor), an inhibitor of hydroxymethylglutaryl co-enzyme A (HMG-CoA) reductase that is a rate-limiting enzyme of mevalonate pathway, down-regulates expression of PBK by impairing protein geranylgeranylation...
2015: Cancer Cell International
https://www.readbyqxmd.com/read/25330763/inhibiting-geranylgeranyltransferase-i-activity-decreases-spine-density-in-central-nervous-system
#19
Maochun Yuan, Shangfeng Gao, Chengdong Sun, Long Chen, Qiong Shi, Jinxia Hu, Rutong Yu, Xiuping Zhou
Geranylgeranyltransferase I (GGT), a protein prenyltransferase, is responsible for the posttranslational lipidation of Rho GTPases, such as Rac, Rho and Cdc42, all of which play an important role in neuronal synaptogenesis. We previously demonstrated that GGT promotes dendritic morphogenesis in cultured hippocampal neurons and cerebellar slices. We report here that inhibiting GGT activity decreases basal- and activity-dependent changes in spine density as well as in learning and memory ability of mice in vivo...
March 2015: Hippocampus
https://www.readbyqxmd.com/read/24964743/statin-induced-inhibition-of-breast-cancer-proliferation-and-invasion-involves-attenuation-of-iron-transport-intermediacy-of-nitric-oxide-and-antioxidant-defence-mechanisms
#20
Anantha Koteswararao Kanugula, Paradesi Naidu Gollavilli, Sathish Babu Vasamsetti, Santosh Karnewar, Raja Gopoju, Ramesh Ummanni, Srigiridhar Kotamraju
Accumulating evidence from in vitro, in vivo, clinical and epidemiological studies shows promising results for the use of statins against many cancers including breast carcinoma. However, the molecular mechanisms responsible for the anti-proliferative and anti-invasive properties of statins still remain elusive. In this study, we investigated the involvement of nitric oxide, iron homeostasis and antioxidant defence mechanisms in mediating the anti-proliferative and anti-invasive properties of hydrophobic statins in MDA-MB-231, MDA-MB-453 and BT-549 metastatic triple negative breast cancer cells...
August 2014: FEBS Journal
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