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K Kranthi Kumar, B Uma Devi, P Neeraja
In this study, cholesterol biotransformation gene-set of human steroidogenic acute regulatory protein-related lipid transfer (START) domains were evaluated from high-throughput gene screening approaches. It was shown that STARD1, STARD3 and STARD4 proteins are better effective transporters of cholesterol than STARD5 and STARD6 domains. Docking studies show a strong agreement with gene ontology enrichment data. According to both complementary strategies, it was found that only STARD1, STARD3 and STARD4 are potentially involved in cholesterol biotransformation in mitochondria through Ω1-loop of C-terminal α4-helical domain...
June 2018: SAR and QSAR in Environmental Research
Martin Perreault, René Maltais, Lucie Carolle Kenmogne, Danny Létourneau, Jean-Guy LeHoux, Stéphane Gobeil, Donald Poirier
The aminosteroid derivative RM-133 is an effective anticancer molecule for which proof of concept has been achieved in several mouse xenograph models (HL-60, MCF-7, PANC-1 and OVCAR-3). To promote this new family of molecules toward a clinical phase 1 trial, the mechanism of action governing the anticancer properties of the representative candidate RM-133 needs to be characterized. In vitro experiments were first used to determine that RM-133 causes apoptosis in cancer cells. Then, using proteomic and transcriptomic experiments, RM-133 cytotoxicity was proven to be achieved via the endoplasmic reticulum (ER)-related apoptosis, which characterizes RM-133 as an endoplasmic reticulum stress aggravator (ERSA) anticancer drug...
February 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Danny Létourneau, Andrée Lefebvre, Pierre Lavigne, Jean-Guy LeHoux
Steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain proteins display diverse expression patterns and cellular localisations. They bind a large variety of lipids and sterols and are involved in lipid metabolism, lipid transfer and cell signalling. The START domain tertiary structure is an α-helix/β-grip fold module of approximately 210 amino acids delimiting an internal cavity forming the binding site. However, the determinants that dictate ligand specificity and the mechanism of ligand entry and exit are ill-defined...
June 15, 2015: Molecular and Cellular Endocrinology
Wenbo Tang, Matthew Kowgier, Daan W Loth, María Soler Artigas, Bonnie R Joubert, Emily Hodge, Sina A Gharib, Albert V Smith, Ingo Ruczinski, Vilmundur Gudnason, Rasika A Mathias, Tamara B Harris, Nadia N Hansel, Lenore J Launer, Kathleen C Barnes, Joyanna G Hansen, Eva Albrecht, Melinda C Aldrich, Michael Allerhand, R Graham Barr, Guy G Brusselle, David J Couper, Ivan Curjuric, Gail Davies, Ian J Deary, Josée Dupuis, Tove Fall, Millennia Foy, Nora Franceschini, Wei Gao, Sven Gläser, Xiangjun Gu, Dana B Hancock, Joachim Heinrich, Albert Hofman, Medea Imboden, Erik Ingelsson, Alan James, Stefan Karrasch, Beate Koch, Stephen B Kritchevsky, Ashish Kumar, Lies Lahousse, Guo Li, Lars Lind, Cecilia Lindgren, Yongmei Liu, Kurt Lohman, Thomas Lumley, Wendy L McArdle, Bernd Meibohm, Andrew P Morris, Alanna C Morrison, Bill Musk, Kari E North, Lyle J Palmer, Nicole M Probst-Hensch, Bruce M Psaty, Fernando Rivadeneira, Jerome I Rotter, Holger Schulz, Lewis J Smith, Akshay Sood, John M Starr, David P Strachan, Alexander Teumer, André G Uitterlinden, Henry Völzke, Arend Voorman, Louise V Wain, Martin T Wells, Jemma B Wilk, O Dale Williams, Susan R Heckbert, Bruno H Stricker, Stephanie J London, Myriam Fornage, Martin D Tobin, George T O'Connor, Ian P Hall, Patricia A Cassano
BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function...
2014: PloS One
Ning Li, Jin-Lin Hou, Zhi-Zhou Shi, Xiao-Guang Li, Nan Li, Yang-Chun Sun, Xin Xu, Yan Cai, Xun Zhang, Kai-Tai Zhang, Ming-Rong Wang, Ling-Ying Wu
For advanced epithelial ovarian cancer (EOC), time to recurrence (TTR) is an important indicator to gauge the therapeutic efficacy of postoperative adjuvant chemotherapy. Our objective was to determine the genes that could potentially distinguish patients with short versus long TTR after initial administration of platinum-paclitaxel combination chemotherapy in advanced EOC. Tumor samples of 159 patients were obtained during the primary cytoreduction. Array comparative genomic hybridization (CGH) was carried with genomic DNA from 17 EOC samples (8 with TTR > 15 months and 9 with TTR ≤ 6 months) to screen candidate gene set, copy-number changes (CNC) of which were significantly different between early and late relapse cases...
2014: American Journal of Cancer Research
Maria Calderon-Dominguez, Gregorio Gil, Miguel Angel Medina, William M Pandak, Daniel Rodríguez-Agudo
Cholesterol levels in the body are maintained through the coordinated regulation of its uptake, synthesis, distribution, storage and efflux. However, the way cholesterol is sorted within cells remains poorly defined. The discovery of the newly described StarD4 subfamily, part of the steroidogenic acute regulatory lipid transfer (START) domain family of proteins, affords an opportunity for the study of intracellular cholesterol movement, metabolism and its disorders. The three members of this intracellular subfamily of proteins (StarD4, StarD5 and StarD6) have a similar lipid binding pocket specific for sterols (cholesterol in particular), but differing regulation and localization...
April 2014: International Journal of Biochemistry & Cell Biology
Danny Létourneau, Aurélien Lorin, Andrée Lefebvre, Jérôme Cabana, Pierre Lavigne, Jean-Guy LeHoux
STARD5 is a member of the STARD4 sub-family of START domain containing proteins specialized in the non-vesicular transport of lipids and sterols. We recently reported that STARD5 binds primary bile acids. Herein, we report on the biophysical and structural characterization of the binding of secondary and conjugated bile acids by STARD5 at physiological concentrations. We found that the absence of the 7α-OH group and its epimerization increase the affinity of secondary bile acids for STARD5. According to NMR titration and molecular modeling, the affinity depends mainly on the number and positions of the steroid ring hydroxyl groups and to a lesser extent on the presence or type of bile acid side-chain conjugation...
November 2013: Biochimica et Biophysica Acta
Danny Létourneau, Andrée Lefebvre, Pierre Lavigne, Jean-Guy LeHoux
We present herein a review of our recent results on the characterization of the binding sites of STARD1, STARD5 and STARD6 using NMR and other biophysical techniques. Whereas STARD1 and STARD6 bind cholesterol, no cholesterol binding could be detected for STARD5. However, titration of STARD5 with cholic acid and chenodeoxycholic acid led to specific binding. Using perturbation of the (1)H-(15)N-HSQC spectra and the sequence specific NMR assignments, we identified the amino acids in contact with those ligands...
May 22, 2013: Molecular and Cellular Endocrinology
Daniel Rodriguez-Agudo, Maria Calderon-Dominguez, Miguel Angel Medina, Shunlin Ren, Gregorio Gil, William M Pandak
StarD5 belongs to the StarD4 subfamily of steroidogenic acute regulatory lipid transfer (START) domain proteins. In macrophages, StarD5 is found in the cytosol and maintains a loose association with the Golgi. Like StarD1 and StarD4, StarD5 is known to bind cholesterol. However, its function and regulation remain poorly defined. Recently, it has been shown that its mRNA expression is induced in response to different inducers of endoplasmic reticulum (ER) stress. However, the molecular mechanism(s) involved in the induction of StarD5 expression during ER stress is not known...
December 2012: Journal of Lipid Research
Danny Létourneau, Aurélien Lorin, Andrée Lefebvre, Vincent Frappier, Francis Gaudreault, Rafael Najmanovich, Pierre Lavigne, Jean-Guy LeHoux
Steroidogenic acute regulatory-related lipid transfer (START) domain proteins are involved in the nonvesicular intracellular transport of lipids and sterols. The STARD1 (STARD1 and STARD3) and STARD4 subfamilies (STARD4-6) have an internal cavity large enough to accommodate sterols. To provide a deeper understanding on the structural biology of this domain, the binding of sterols to STARD5, a member of the STARD4 subfamily, was monitored. The SAR by NMR [(1)H-(15)N heteronuclear single-quantum coherence (HSQC)] approach, complemented by circular dichroism (CD) and isothermal titration calorimetry (ITC), was used...
December 2012: Journal of Lipid Research
Aurélien Lorin, Danny Létourneau, Andrée Lefebvre, Jean-Guy LeHoux, Pierre Lavigne
Steroidogenic acute regulatory (StAR)-related lipid transfer proteins possess a START (steroidogenic acute regulatory-related lipid transfer) domain. START domains are conserved protein modules involved in the non-vesicular intracellular transport of lipids and cholesterol in mammals. Fifteen mammalian proteins, divided in five subfamilies, are reported to possess a START domain. Members of the STARD4 subfamily, i.e. STARD4, 5 and 6 are essentially single START domains and are thought to be involved in the intracellular transport of cholesterol...
April 2013: Biomolecular NMR Assignments
Ann-Gerd Thorsell, Wen Hwa Lee, Camilla Persson, Marina I Siponen, Martina Nilsson, Robert D Busam, Tetyana Kotenyova, Herwig Schüler, Lari Lehtiö
BACKGROUND: Steroidogenic acute regulatory (StAR) protein related lipid transfer (START) domains are small globular modules that form a cavity where lipids and lipid hormones bind. These domains can transport ligands to facilitate lipid exchange between biological membranes, and they have been postulated to modulate the activity of other domains of the protein in response to ligand binding. More than a dozen human genes encode START domains, and several of them are implicated in a disease...
2011: PloS One
Pierre Lavigne, Rafael Najmanivich, Jean-Guy Lehoux
The StAR-related lipid transfer (START) domain is an evolutionary conserved protein module of approximately 210 amino acids. There are 15 mammalian proteins that possess a START domain. Whereas the functions and specific ligands are being elucidated, 5 of them have already been shown to bind specifically cholesterol. The most intensively studied member of this subclass is the steroidogenic acute regulatory protein (StAR) or STARD1. While its role in steroid hormone production has been demonstrated, much less is understood about how its START domain specifically recognizes cholesterol and how it releases it to be transferred inside the mitochondria of steroidogenic cell of the gonads and adrenal cortex...
2010: Sub-cellular Biochemistry
Joshua J Riegelhaupt, Marc P Waase, Jeanne Garbarino, Daniel E Cruz, Jan L Breslow
Steroidogenic acute regulatory protein (StAR)D4 is a member of the StAR related lipid transfer family. Homology comes from the approximately 210 amino acid lipid binding domain implicated in intracellular transport, cell signaling, and lipid metabolism. StARD4 was identified as a gene downregulated 2-fold by dietary cholesterol (Soccio, R. E., R. M. Adams, K. N. Maxwell, and J. L. Breslow. 2005. Differential gene regulation of StarD4 and StarD5 cholesterol transfer proteins. Activation of StarD4 by sterol regulatory element-binding protein-2 and StarD5 by endoplasmic reticulum stress...
May 2010: Journal of Lipid Research
Yu-Chyu Chen, Renate K Meier, Shirong Zheng, Syed J Khundmiri, Michael T Tseng, Eleanor D Lederer, Paul N Epstein, Barbara J Clark
STARD5 is a cytosolic sterol transport protein that is predominantly expressed in liver and kidney. This study provides the first report on STARD5 protein expression and distribution in mouse kidney. Immunohistochemical analysis of C57BL/6J mouse kidney sections revealed that STARD5 is expressed in tubular cells within the renal cortex and medullar regions with no detectable staining within the glomeruli. Within the epithelial cells of proximal renal tubules, STARD5 is present in the cytoplasm with high staining intensity along the apical brush-border membrane...
August 2009: American Journal of Physiology. Renal Physiology
Fabien Alpy, François Legueux, Laurent Bianchetti, Catherine Tomasetto
Fifteen START domain-containing proteins exist in mammals. On the basis of their structural homology, this family is divided into several sub-families consisting mainly of non-vesicular intracellular lipid carriers. With the exception of the Thioesterase-START subfamily, the other subfamilies are represented among invertebrates. The START domain is always located in the C-terminus of the protein. It is a module of about 210 residues that binds lipids, including sterols. Cholesterol, 25-hydroxycholesterol, phosphatidylcholine, phosphatidylethanolamine and ceramides are ligands for STARD1/STARD3-6, STARD5, STARD2/STARD10, STARD10 and STARD11, respectively...
February 2009: Médecine Sciences: M/S
Daniel Rodriguez-Agudo, Shunlin Ren, Eric Wong, Dalila Marques, Kaye Redford, Gregorio Gil, Phillip Hylemon, William M Pandak
StarD4 protein is a member of the StarD4 subfamily of steroidogenic acute regulatory-related lipid transfer (START) domain proteins that includes StarD5 and StarD6, proteins whose functions remain poorly defined. The objective of this study was to isolate and characterize StarD4's sterol binding and to determine in a hepatocyte culture model its sterol transport capabilities. Utilizing purified full-length StarD4, in vitro binding assays demonstrated a concentration-dependent binding of [(14)C]cholesterol by StarD4 similar to that of the cholesterol binding START domain proteins StarD1 and StarD5...
July 2008: Journal of Lipid Research
Tomomoto Ishikawa, Patricia L Morris
Our recent Sertoli cell (SC) studies showed that the c-Jun N-terminal kinase (JNK) and inducible cyclooxygenase-2 (COX-2) pathways are key regulatory components of IL (IL-1alpha, IL-1beta, and IL-6) expression and START-domain containing StARD1 and StARD5 proteins. IL-1beta regulates SC autocrine/paracrine activities and subsequently influences developing germ cells and spermatogenesis. This study was designed to evaluate whether IL-1beta mediates high-output inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production in these specialized epithelial cells and characterize gonadotropin and cytokine-regulation of NO...
November 2006: Endocrinology
Daniel Rodriguez-Agudo, Shunlin Ren, Phillip B Hylemon, Raul Montañez, Kaye Redford, Ramesh Natarajan, Miguel Angel Medina, Gregorio Gil, William M Pandak
Human StarD5 belongs to the StarD4 subfamily of START (for steroidogenic acute regulatory lipid transfer) domain proteins. We previously reported that StarD5 is located in the cytosolic fraction of human liver and binds cholesterol and 25-hydroxycholesterol. After overexpression of the gene encoding StarD5 in primary rat hepatocytes, free cholesterol accumulated in intracellular membranes. These findings suggested StarD5 to be a directional cytosolic sterol transporter. The objective of this study was to determine the localization of StarD5 in human liver...
June 2006: Journal of Lipid Research
Tomomoto Ishikawa, Keumsil Hwang, Deborah Lazzarino, Patricia L Morris
In testicular Sertoli cells, IL-1beta regulates steroid, lactate, and transferrin secretion; although each influences germ cell development and spermatogenesis, little is known about the signaling mechanisms involved. In other cell types, IL-1beta potently induces reactive oxygen species and/or cyclooxygenase-2 (COX-2). In contrast, in Sertoli cells, IL-1beta does not generate reactive oxygen species, but rapidly phosphorylates c-Jun-NH(2)-terminal kinase (JNK), but not p44/42 or p38 MAPK. Phosphorylated JNK stimulates COX-2 activity, mediating the expression of ILs and steroidogenic acute regulatory (StAR)-related (StAR-related lipid transfer protein domain containing) proteins D1 and D5, but not D4...
December 2005: Endocrinology
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