He, Xin
(2008)
Role of PIK3IP1, a negative PI3K regulator, in hepatic tumorigenesis and metabolism.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Phosphatidylinositol-3-kinase (PI3K) is a well-known regulator of cell division, motility, metabolism and survival in most cell types. Proper liver function and development highly depend on intact PI3K signal transduction. Aberrant PI3K pathway signaling in the liver is associated with hepatocellular carcinoma (HCC). In addition, PI3K signaling is involved in the homeostasis of lipid and glucose metabolism. Activation of the PI3K pathway induces lipogenesis and glycogenesis in the liver, since both Akt overexpressing transgenic mice and PTEN knockout mice develop fatty liver and hypoglycemia. Our laboratory characterized a novel protein that we call PI3K Interacting Protein 1 (PIK3IP1) which binds to the p110 catalytic subunit of PI3K and reduces its activity in vitro. Little is known about PIK3IP1's role in tumorigenesis and metabolism in vivo. Therefore we constructed PIK3IP1 transgenic mice (TG) which overexpress PIK3IP1 in hepatocytes under an albumin promoter in the C3H mouse strain to investigate the effect of PIK3IP1 on hepatocyte growth and metabolism, as well as HCC tumorigenesis. We detected a high expression level of PIK3IP1 in the livers from TG animals. The PI3K pathway was successfully suppressed both in liver tissues and isolated hepatocytes, which was confirmed by Western blots and phospho-protein array studies. Given the fact that PI3K signaling is associated with liver tumorigenesis, our next objective was to determine whether PIK3IP1 inhibits HCC development through PIK3IP1- mediated downregulation of the PI3K pathway. In vivo, spontaneous liver tumorigenesis was significantly dampened in the transgenic animals. This was accompanied by decreased hepatic PI3K activity and reduced hepatocyte proliferation in the transgenics as compared to controls. Isolated PIK3IP1 transgenic mouse hepatocytes showed blunted PI3K signaling, DNA synthetic activity, motility and survival as compared to controls. We then investigated the effect of PIK3IP1 on the maintenance of whole-body glucose and fat homeostasis. We observed that mice overexpressing PIK3IP1 have increased body weight, hyperglycemia, as well as increased visceral fat deposition. This suggests PIK3IP1 is an important regulator of metabolism. In conclusion, we successfully generated a transgenic mouse model with PIK3IP1 overexpression in hepatocytes to assess the biological functions of PIK3IP1, an important negative regulator of PI3K, in liver tumorigenesis and insulin signaling. A high level expression of PIK3IP1 suppressed PI3K signaling pathway in vivo and in vitro, which curbs hepatic tumorigenesis. Furthermore, we show that PIK3IP1 overexpression can contribute to glucose homeostasis and fatty deposition.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
19 June 2008 |
| Date Type: |
Completion |
| Defense Date: |
24 April 2008 |
| Approval Date: |
19 June 2008 |
| Submission Date: |
2 June 2008 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cellular and Molecular Pathology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
HCC; liver; PI3K; PIK3IP1 |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-06022008-121738/, etd-06022008-121738 |
| Date Deposited: |
10 Nov 2011 19:46 |
| Last Modified: |
19 Dec 2016 14:36 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/7991 |
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