The rough endoplasmic reticulum (ER) serves as the entry point into the secretory pathway for newly-synthesized hormones and enzymes. Accordingly, the rough ER mediates highly-efficient translocation of nascent polypeptides from the cytoplasm into its lumen. In tissues where high levels of secretion are demanded, the rough ER is so abundant that it dominates the sub-cellular landscape. Proliferation of ER is induced in cells and tissues in response to intoxication, or when cells are stimulated to secrete large quantities of proteins. It is the purpose of the research described here to focus on the mechanism of how stimulated proliferation of the rough ER is accomplished. Bound ribosomes represent the distinguishing feature of rough ER. A mammalian rough ER-specific protein that was previously isolated and characterized as having a high-affinity for ribosomes and a remarkable primary structure induces rough membrane proliferation upon its expression in yeast and mammalian cells. The hypothesis that there is a specific signaling pathway leading to ER membrane proliferation can now be tested in model systems using a balance of biochemical, cell biological and genetic approaches. Factors will be identified and characterized that enable cells, from yeast to mammals, to upregulate their mass of rough ER. Preliminary results indicate that in yeast, it is possible to upregulate the entire secretory pathway, thus paving the way for an investigation of the regulation of this complex and important intracellular pathway in a genetically-tractable organism.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM038538-11
Application #
6018694
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1987-09-01
Project End
2002-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
11
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Biochemistry
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Benyamini, Payam; Webster, Paul; Meyer, David I (2009) Knockdown of p180 eliminates the terminal differentiation of a secretory cell line. Mol Biol Cell 20:732-44
Hyde, Maureen; Block-Alper, Laura; Felix, Jahaira et al. (2002) Induction of secretory pathway components in yeast is associated with increased stability of their mRNA. J Cell Biol 156:993-1001
Becker, F; Block-Alper, L; Nakamura, G et al. (1999) Expression of the 180-kD ribosome receptor induces membrane proliferation and increased secretory activity in yeast. J Cell Biol 146:273-84
Wanker, E E; Sun, Y; Savitz, A J et al. (1995) Functional characterization of the 180-kD ribosome receptor in vivo. J Cell Biol 130:29-39
Mayinger, P; Bankaitis, V A; Meyer, D I (1995) Sac1p mediates the adenosine triphosphate transport into yeast endoplasmic reticulum that is required for protein translocation. J Cell Biol 131:1377-86
Savitz, A J; Meyer, D I (1993) 180-kD ribosome receptor is essential for both ribosome binding and protein translocation. J Cell Biol 120:853-63
Bush, G L; Tassin, A M; Friden, H et al. (1991) Secretion in yeast. Purification and in vitro translocation of chemical amounts of prepro-alpha-factor. J Biol Chem 266:13811-4
Sanderson, C M; Meyer, D I (1991) Purification and functional characterization of membranes derived from the rough endoplasmic reticulum of Saccharomyces cerevisiae. J Biol Chem 266:13423-30
Sanderson, C M; Crowe, J S; Meyer, D I (1990) Protein retention in yeast rough endoplasmic reticulum: expression and assembly of human ribophorin I. J Cell Biol 111:2861-70
Sanz, P; Meyer, D I (1989) Secretion in yeast: preprotein binding to a membrane receptor and ATP-dependent translocation are sequential and separable events in vitro. J Cell Biol 108:2101-6

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