This project is concerned with mechanisms underlying osteoblast differentiation, a critical process during bone remodeling and repair. In this dissertation I explored novel regulators for osteoblast differentiation by identifying functional partners of ATF4, an osteoblast-enriched transcription factor important for osteoblast differentiation and bone formation. Through a combination of biochemical, molecular and cellular experiments, I identified and confirmed vimentin, an intermediate filament protein, as a novel inhibitor for ATF4's transcriptional activity and osteoblast differentiation. Furthermore, through series of genetic and pharmacological interventions in vitro and in vivo, I revealed that the vimentin serves as a downstream mediator that responds TGF beta signaling by binding and inhibiting ATF4 in immure osteoblasts via a non-canonical pathway. Therefore, this research uncovers a novel mechanism by which a cytoskeletal protein, vimentin, acts as a brake on differentiation in immature osteoblasts by its interaction with ATF4.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03262011-122546 |
| Date | 14 April 2011 |
| Creators | Lian, Na |
| Contributors | Xiangli Yang, Vsevolod Gurevich, Florent Elefteriou, Douglas Mortlock, Eugenia Gurevich, Linda Sealy |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03262011-122546/ |
| 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 Vanderbilt University 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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