Research Overview
Protein Processing
Modification of proteins with a conserved polypeptide called
ubiquitin regulates many aspects of cell biology and is involved in the
pathogenesis of many diseases. This modification process is known as
ubiquitination and is catalyzed by three enzymes, one of which is a family of
enzymes called ubiquitin ligase. There
are hundreds of predicted ubiquitin ligases in the DNA database. However, to date, the majority of the
ubiquitin ligases have not been investigated.
My lab focuses on the endoplasmic reticulum-resident
ubiquitin ligase gp78 and its related proteins. ...
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Research Description
Research Specialties: Ubiquitination, Protein Degradation, RING Finger Proteins
My laboratory studies the functions of the ubiquitin system, with special emphasis on the endoplasmic reticulum-associated protein degradation (ERAD). Ubiquitin regulates cellular functions through ubiquitination, a process that provides eukaryotic cells with a means to fine-tune both protein function and levels. Ubiquitination affects myriad proteins and potentially impacts all cellular processes. Our research has high relevance to human health, because there is growing evidence that dysfunction of the ubiquitin system and ERAD are intimately involved in the pathogenesis of many human diseases, including cancer, diabetes, cystic fibrosis, heart disease, and neurodegenerative diseases.
gp78 and ER-associated degradation
ERAD safeguards the secretory pathway through eliminating misfolded and unassembled proteins from the ER. It also regulates many physiological processes through regulated-degradation of key proteins. For example, ERAD is essential for sterol-regulated degradation of HMG CoA reductase, a rate-limiting enzyme in cholesterol synthesis. Accelerated degradation of the reductase is one of the several strategies cells use to limit the production of cholesterol. We have identified gp78 as the first ER-resident ubiquitin ligase involved in ubiquitination of unwanted proteins during ERAD. Recently, work from my laboratory...
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Representative Publications
Yang, Y., Fang, S., Jensen, J. P., Weissman, A. M., and Ashwell, J. D.
(2000). Ubiquitin Protein Ligase Activity of IAPs and Their Degradation
in Proteasomes in Response to Apoptotic Stimuli. Science 288, 874-877.
Fang,
S., Jensen, J. P., Ludwig, R. L., Vousden, K. H., and Weissman, A. M.
(2000). Mdm2 is a RING finger-dependent ubiquitin protein ligase for
itself and p53. J Biol Chem 275, 8945-8951.
Fang, S., Ferrone,
M., Yang, C., Jensen, J. P., Tiwari, S., and Weissman, A.M. (2001)
gp78, the tumor autocrine motility factor receptor, mediates
degradation from the endoplasmic reticulum in human cells. Proc Natl
Acad Sci U S A 98, 14422-14427.
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