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 PIK3IP1s 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.
Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-06022008-121738 |
Date | 19 June 2008 |
Creators | He, Xin |
Contributors | Donna B. Stolz, Ph.D., Marie C. DeFrances, M.D., Ph.D., George K. Michalopoulos, M.D., Ph.D., Satdarshan Pal Singh Monga, M.D., Stephen Strom, Ph.D. |
Publisher | University of Pittsburgh |
Source Sets | University of Pittsburgh |
Language | English |
Detected Language | English |
Type | text |
Format | application/pdf |
Source | http://etd.library.pitt.edu/ETD/available/etd-06022008-121738/ |
Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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