Abstract

Hormone biosynthesis requires the selective packaging of hormones into secretory vesicles. The grant focuses on the budding of secretory vesicles from the trans Golgi network (TGN), and the roles of phospholipid metabolism and protein factor in that budding. Eventual goals include rational drug design to treat pathological conditions of hormone secretion. The basic scheme being pursued involves activation of phospholipase D in the TGN by ADP-ribosylation factor-1 (ARF-1). Then phospholipase D (PLD) in turn generates phosphatidic acid (PA).
Aim 1 : The role of PA accumulation in regulating the biosynthesis of phosphatidylinositol 4,5 bisphosphate (PIP2) will be examined. The hypothesis is that PA regulates PIP2, which controls budding from the TGN and also maintenance of Golgi architecture.
Aim 2 :
Aim 1 will be extended to other cells to see what aspects of hormone secretion, Golgi morphology, constitutive secretion, and lysosomal vesicle release depends on PA production.
Aim 3 : Purification of protein factors, which promote vesicle budding, will be pursued using standard protein purification approaches. The hypothesis is that PLD is recruited to the TGN and activated via a protein complex consisting of ARF-1 and other proteins. Native and epitope tagged versions of ARF-1 will be used in conjunction with cross-linking agents to identify the proposed protein complex.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK021860-26
Application #
6634858
Study Section
Endocrinology Study Section (END)
Program Officer
Haft, Carol R
Project Start
1978-07-01
Project End
2004-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
26
Fiscal Year
2003
Total Cost
$584,294
Indirect Cost

  Institution

Name
Albert Einstein College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
071036636
City
Bronx
State
NY
Country
United States
Zip Code
10461

  Publications

Bejarano, Eloy; Yuste, Andrea; Patel, Bindi et al. (2014) Connexins modulate autophagosome biogenesis. Nat Cell Biol 16:401-14
Schneider, Jaime L; Cuervo, Ana Maria (2014) Liver autophagy: much more than just taking out the trash. Nat Rev Gastroenterol Hepatol 11:187-200
Radulescu, Andreea E; Shields, Dennis (2012) Clathrin is required for postmitotic Golgi reassembly. FASEB J 26:129-36
Radulescu, Andreea E; Mukherjee, Shaeri; Shields, Dennis (2011) The Golgi protein p115 associates with gamma-tubulin and plays a role in Golgi structure and mitosis progression. J Biol Chem 286:21915-26
How, Poh Choo; Shields, Dennis (2011) Tethering function of the caspase cleavage fragment of Golgi protein p115 promotes apoptosis via a p53-dependent pathway. J Biol Chem 286:8565-76
Riebeling, Christian; Morris, Andrew J; Shields, Dennis (2009) Phospholipase D in the Golgi apparatus. Biochim Biophys Acta 1791:876-80
Mukherjee, Shaeri; Shields, Dennis (2009) Nuclear import is required for the pro-apoptotic function of the Golgi protein p115. J Biol Chem 284:1709-17
Riebeling, Christian; Bourgoin, Sylvain; Shields, Dennis (2008) Caspase cleavage of phospholipase D1 in vitro alters its regulation and reveals a novel property of the ""loop"" region. Biochim Biophys Acta 1781:376-82
Mukherjee, Shaeri; Chiu, Raymond; Leung, Som-Ming et al. (2007) Fragmentation of the Golgi apparatus: an early apoptotic event independent of the cytoskeleton. Traffic 8:369-78
Radulescu, Andreea E; Siddhanta, Anirban; Shields, Dennis (2007) A role for clathrin in reassembly of the Golgi apparatus. Mol Biol Cell 18:94-105

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