This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Sphingolipids (SLs) mediate cellular activities including apoptosis. The first and rate-limiting step in de novo synthesis of SLs is through serine palmitoyltransferase (SPT), which condenses serine with palmitoyl-CoA, producing a sphingoid base, the backbone of all SLs. Importantly, many stimuli induce de novo synthesis of SLs, including chemotherapy, but the mechanisms are unknown. We have preliminary data that in yeast, heat stress stimulates de novo SL synthesis by stimulating serine uptake from media. Moreover, the fatty acid component for de novo synthesis derives from endogenous synthesis via fatty acid synthase (FAS). Based on these findings, we hypothesize that regulation of substrate supply serves to modulate de novo synthesis of SLs in response to stimuli including chemotherapeutic agents. Therefore, the aims of this proposal are: 1) to determine the mechanisms required for heat stress stimulation of exogenous serine uptake in yeast;2) to determine the role of FAS and acyl-CoA synthetase in heat-stres induced SPT activity. These 2 aims will be accomplished using a multifaceted approach with yeast genetic sreens, in vitro enzyme activity determinations, and lipid analysis;and 3)to determine the role of substrate supply in cancer cells in response to chemotherapeutic agents. In this aim, we will focus on gemcitabine, which activates the de novo pathway in A549 cells, leading to alternative splicing of pro-apoptotic factors. We hypothesize that substrate availability may regulate gemcitabine-induced de novo SL synthesis, which would allow novel approaches to chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR017677-10
Application #
8360380
Study Section
Special Emphasis Panel (ZRR1-RI-5 (01))
Project Start
2011-07-01
Project End
2012-07-18
Budget Start
2011-07-01
Budget End
2012-07-18
Support Year
10
Fiscal Year
2011
Total Cost
$72,285
Indirect Cost
Name
Medical University of South Carolina
Department
Biochemistry
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Zunke, Friederike; Moise, Alexandra C; Belur, Nandkishore R et al. (2018) Reversible Conformational Conversion of ?-Synuclein into Toxic Assemblies by Glucosylceramide. Neuron 97:92-107.e10
Vilaça, Rita; Barros, Ivo; Matmati, Nabil et al. (2018) The ceramide activated protein phosphatase Sit4 impairs sphingolipid dynamics, mitochondrial function and lifespan in a yeast model of Niemann-Pick type C1. Biochim Biophys Acta Mol Basis Dis 1864:79-88
Chen, Wei; Wang, Bo; Gruber, Jordon D et al. (2018) Acyl Carrier Protein 3 Is Involved in Oxidative Stress Response in Pseudomonas aeruginosa. Front Microbiol 9:2244
Fekry, Baharan; Jeffries, Kristen A; Esmaeilniakooshkghazi, Amin et al. (2018) C16-ceramide is a natural regulatory ligand of p53 in cellular stress response. Nat Commun 9:4149
Jin, Junfei; Lu, Zhongyang; Li, Yanchun et al. (2018) LPS and palmitate synergistically stimulate sphingosine kinase 1 and increase sphingosine 1 phosphate in RAW264.7 macrophages. J Leukoc Biol 104:843-853
Snider, Justin M; Snider, Ashley J; Obeid, Lina M et al. (2018) Probing de novo sphingolipid metabolism in mammalian cells utilizing mass spectrometry. J Lipid Res 59:1046-1057
Zhang, Ning; Valentine, Joseph M; Zhou, You et al. (2017) Sustained NF?B inhibition improves insulin sensitivity but is detrimental to muscle health. Aging Cell 16:847-858
Pulkoski-Gross, Michael J; Uys, Joachim D; Orr-Gandy, K Alexa et al. (2017) Novel sphingosine kinase-1 inhibitor, LCL351, reduces immune responses in murine DSS-induced colitis. Prostaglandins Other Lipid Mediat 130:47-56
Alexaki, Aikaterini; Clarke, Benjamin A; Gavrilova, Oksana et al. (2017) De Novo Sphingolipid Biosynthesis Is Required for Adipocyte Survival and Metabolic Homeostasis. J Biol Chem 292:3929-3939
Hao, Limin; Ben-David, Oshrit; Babb, Suzann M et al. (2017) Clozapine Modulates Glucosylceramide, Clears Aggregated Proteins, and Enhances ATG8/LC3 in Caenorhabditis elegans. Neuropsychopharmacology 42:951-962

Showing the most recent 10 out of 196 publications