التفاصيل البيبلوغرافية
| العنوان: |
The Pathologic and Physiologic Role of SOCS-3 in Liver Metabolism |
| المؤلفون: |
Gaudy, Allison M., Mooney, Robert A. |
| سنة النشر: |
2013 |
| المجموعة: |
University of Rochester, New York: UR Research |
| مصطلحات موضوعية: |
SOCS-3, Gluconeogenesis, Epac |
| الوصف: |
Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Pharmacology and Physiology, 2010. ; Suppressor of cytokine signaling (SOCS-3) is a signal transducer and activator of transcription (STAT-3) induced negative regulator of janus kinase (JAK)/STAT signaling. Obesity-related increases in circulating IL-6 increase hepatic SOCS-3 levels, and are associated with the development of insulin resistance. Recently, SOCS-3 has been shown to be induced by a cAMP-dependent pathway involving Epac (exchange protein directly activated by cAMP). This thesis examines the physiologic and pathologic role of SOCS-3 in regulating hepatic glucose metabolism. SOCS-3 inhibits the insulin signaling pathway by inhibition and degradation of insulin receptor substrates (IRS-1 and IRS-2). SOCS-3 contains a src homology (SH-2) domain that binds to tyrosine phosphorylated IRS proteins, and a C-terminal SOCS box that contains E3 ligase activity that mediates ubiquitination and degradation of IRS. There are conflicting reports, however, on the mechanism by which SOCS-3 mediates its inhibition in the various insulin responsive tissues. To investigate the role of SOCS-3 in modulating hepatic insulin signaling, hepatic suppression of SOCS-3 was attained by adenovirus delivery of a shRNA construct to the liver of both lean and obese mice. SOCS-3 suppression increased IRS-1 and AKT phosphorylation both basally and after an insulin bolus in lean and obese mice. IRS-1 and IRS-2 protein levels were unaltered in lean mice. In contrast, IRS-1 protein levels increased 80% in obese animals, without changes in messenger RNA levels. IRS-2 phosphorylation and protein levels were unaltered. These data demonstrate that SOCS-3 differentially regulates IRS-1 and IRS-2 protein in the obese mouse, and that SOCS-3 is capable of modulating insulin signaling in the absence of IRS protein loss in the lean mouse. To determine the mechanism of SOCS-3 degradation of IRS-1 and IRS-2, mouse primary hepatocytes were infected with a SOCS-3 ... |
| نوع الوثيقة: |
thesis |
| اللغة: |
English |
| العلاقة: |
http://hdl.handle.net/1802/13972Test |
| الإتاحة: |
http://hdl.handle.net/1802/13972Test |
| حقوق: |
This item is protected by copyright, with all rights reserved. |
| رقم الانضمام: |
edsbas.A832FB1E |
| قاعدة البيانات: |
BASE |
