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Dissertation
IGF-1 induced IRS-1 degradation in human prostate epithelial cells
Doctor of Philosophy (Ph.D.), Medical College of Pennsylvania and Hahnemann University
Apr 2002
DOI:
https://doi.org/10.17918/00007462
Abstract
IRS-1 is a major early signal mediator of IGF-I and is engaged in various IGF-I stimulated cellular events, including cell proliferation, differentiation and transformation. Considerable evidence suggests that IGF-I plays an important role in tumor cell growth and IRS-1 has been shown to be involved in this process. In our studies, we found that IGF-I stimulation promoted IRS-1 down regulation in human prostate primary cancer epithelial cells. This down regulation occurs primarily through increasing the degradation of IRS-1 proteins, not repressing IRS-1 protein synthesis. We examined potential mechanisms and identified two independent pathways that contributed to this degradation. Using proteasome specific inhibitors-lactocystin and MG132, we found that IRS-1 could be degraded through the 26S proteasome pathway. This result was further confirmed by detectable ubiquitination of IRS-1 proteins in the presence of IGF-I. Furthermore, our studies demonstrated a calcium-dependent calpain digestion of IRS-1 that also occurred during thapsigargin mediated cell apoptosis. Co-precipitation of IRS-1 and calpain proteins was found in the presence or absence of IGF-I. In summary, we identified two important mechanisms for the regulation of IRS-1: targeting to the 26 S proteasome and calpain mediated digestion.
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Details
- Title
- IGF-1 induced IRS-1 degradation in human prostate epithelial cells
- Creators
- Hong Zhang
- Contributors
- Christian Sell (Advisor) - Drexel University, Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Awarding Institution
- Medical College of Pennsylvania and Hahnemann University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Medical College of Pennsylvania and Hahnemann University; Philadelphia, Pennsylvania
- Number of pages
- xiii, 115 pages, 20 unnumbered pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Medicine (1993-1996, 1998-2002); Medical College of Pennsylvania and Hahnemann University (1993-1996, 1998-2002)
- Other Identifier
- 991021888844804721