An analysis of genetic regulation of phospholipid synthesis will be conducted in the unicellular eukaryote, Saccharomyces cerevisiae. A major goal is to develop a comprehensive understanding of the regulatory cascade that controls transcriptional regulation of phospholipid biosynthetic structural genes in response to precursor availability and ongoing phospholipid synthesis. The studies will involve isolation and characterization of mutants with defects in the synthesis and/or regulation of phospholipids. The proposed research also involves a detailed analysis of the transcriptional regulation of structural genes encoding phospholipid biosynthetic enzymes. Four structural genes and three regulatory genes have been isolated and will be used in this analysis. The interaction of the trans-acting regulatory gene products with cis-acting elements in the promoters of the structural genes will be characterized in detail. The cloned structural genes will also be used to facilitate studies of the assembly of the phospholipid biosynthetic enzymes into their specific locations in the cellular membranes. Little is known about the mechanisms by which eukaryotic cells control the synthesis of membrane lipids in coordination with ongoing membrane biogenesis. Yet phospholipids, particularly inositol-containing phospholipids, have been implicated in complex signalling processes which play a role in controlling cell growth and proliferation in higher eukaryotes. Yeast cells synthesize a typically eukaryotic mixture of phospholipids, using pathways which are similar to those in higher eukaryotes. The organism is genetically tractable, and can be manipulated using powerful molecular genetics. Therefore, S. cerevisiae, provides an unusual opportunity to develop a comprehensive understanding of the regulatory mechanisms controlling phospholipid synthesis during membrane biogenesis and cell growth.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM019629-29
Application #
6178839
Study Section
Special Emphasis Panel (NSS)
Program Officer
Chin, Jean
Project Start
1987-09-01
Project End
2001-02-28
Budget Start
2000-09-01
Budget End
2001-02-28
Support Year
29
Fiscal Year
2000
Total Cost
$10,348
Indirect Cost
Name
Carnegie-Mellon University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
052184116
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Gaspar, Maria L; Chang, Yu-Fang; Jesch, Stephen A et al. (2017) Interaction between repressor Opi1p and ER membrane protein Scs2p facilitates transit of phosphatidic acid from the ER to mitochondria and is essential for INO1 gene expression in the presence of choline. J Biol Chem 292:18713-18728
Barneda, David; Planas-Iglesias, Joan; Gaspar, Maria L et al. (2015) The brown adipocyte protein CIDEA promotes lipid droplet fusion via a phosphatidic acid-binding amphipathic helix. Elife 4:e07485
Han, Sungwon; Binns, Derk D; Chang, Yu-Fang et al. (2015) Dissecting seipin function: the localized accumulation of phosphatidic acid at ER/LD junctions in the absence of seipin is suppressed by Sei1p(?Nterm) only in combination with Ldb16p. BMC Cell Biol 16:29
Henry, Susan A; Gaspar, Maria L; Jesch, Stephen A (2014) The response to inositol: regulation of glycerolipid metabolism and stress response signaling in yeast. Chem Phys Lipids 180:23-43
Hofbauer, Harald F; Schopf, Florian H; Schleifer, Hannes et al. (2014) Regulation of gene expression through a transcriptional repressor that senses acyl-chain length in membrane phospholipids. Dev Cell 29:729-39
Lee, Sojin; Gaspar, Maria L; Aregullin, Manuel A et al. (2013) Activation of protein kinase C-mitogen-activated protein kinase signaling in response to inositol starvation triggers Sir2p-dependent telomeric silencing in yeast. J Biol Chem 288:27861-71
Henry, Susan A; Kohlwein, Sepp D; Carman, George M (2012) Metabolism and regulation of glycerolipids in the yeast Saccharomyces cerevisiae. Genetics 190:317-49
Villa-GarcĂ­a, Manuel J; Choi, Myung Sun; Hinz, Flora I et al. (2011) Genome-wide screen for inositol auxotrophy in Saccharomyces cerevisiae implicates lipid metabolism in stress response signaling. Mol Genet Genomics 285:125-49
Gaspar, Maria L; Hofbauer, Harald F; Kohlwein, Sepp D et al. (2011) Coordination of storage lipid synthesis and membrane biogenesis: evidence for cross-talk between triacylglycerol metabolism and phosphatidylinositol synthesis. J Biol Chem 286:1696-708
Jesch, Stephen A; Gaspar, Maria L; Stefan, Christopher J et al. (2010) Interruption of inositol sphingolipid synthesis triggers Stt4p-dependent protein kinase C signaling. J Biol Chem 285:41947-60

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