Cell-matrix and cell-cell adhesion proteins are of great significance for many fundamental cellular processes such as survival, differentiation, spreading, adhesion, migration as well as oncogenic transformation. In the present dissertation study, the role of different integrin-proximal protein complexes was investigated in vitro in cancer cells and in primary rat hepatocytes and in vivo in whole animals.
First it was shown that migfilin, a newly identified cell-matrix adhesion protein, is also an important component of cell-cell junctions critical for the organization and strengthening of the adherens junctions. Next, Ras-Suppressor-1 (RSU-1), which interacts with the focal adhesion protein PINCH, was shown to regulate cell spreading and adhesion, although the exact mechanism is yet unclear.
Furthermore, the role of Integrin-Linked Kinase (ILK) was investigated in vitro in the model system of matrix-induced hepatocyte differentiation. It was shown that ILK along with its binding partners PINCH and Ñ-parvin are dramatically down-regulated during the matrix-induced re-differentiation of hepatocytes. Thus, ILK and its binding partners likely play an important role in matrix-induced-hepatocyte differentiation.
Finally, the role of ILK was examined in vivo by removing the protein from the whole animal or specifically from the liver. First ILK was removed from ILK-floxed mice following Cre-recombinase-adenoviral injections giving rise to animals with fulminant hepatitis characterized by massive apoptosis, abnormal mitoses, fatty change and necrosis in the liver. Then, ILK-floxed animals were crossbred with alpha-fetoprotein(AFP)-albumin, albumin, or Foxa3-Cre transgenic mice and thus ILK was genetically removed specifically from the liver. In all cases, the livers of the animals had disorganized liver architecture, absence of hepatocyte plates, increased fibrosis, absence of microvilli in the canaliculi, different degrees of malformations in the biliary system, apoptosis and compensatory proliferation. The present findings therefore, clearly show that ILK is critical for hepatocyte differentiation and survival and more importantly, this holds true in vivo where ILK is crucial for the maintainance of normal liver architecture and function.
Thus, the present dissertation work highlights the importance of cell-matrix adhesion proteins in vitro and in vivo and enhances the scientific knowledge in the field of molecular, cellular, hepatocyte and liver biology.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-10302006-120358 |
| Date | 03 November 2006 |
| Creators | Gkretsi, Vasiliki |
| Contributors | Donna Beer-Stolz, Satdarshan P. Singh Monga, Chuanyue Wu, Alan Wells, George K. Michalopoulos |
| 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-10302006-120358/ |
| Rights | unrestricted, 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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