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ATF3, a stress-inducible gene: function and regulation

Lu, Dan
http://rave.ohiolink.edu/etdc/view?acc_num=osu1155740569

Abstract Details

2006, Doctor of Philosophy, Ohio State University, Ohio State Biochemistry Program.
Current literature indicates that Activating Transcription Factor 3 (ATF3) affects apoptosis and cell cycle progression, two key processes that regulate tumorigenesis. However, it has been demonstrated to be a negative or positive regulator of these processes. We sought to study the roles of ATF3 in apoptosis, cell cycle regulation, as well tumorigenesis in the same cell type using mouse fibroblasts. I show that ATF3 promotes apoptosis and cell cycle arrest. Consistently, ATF3-/- fibroblasts upon Ras transformation exhibited higher growth rate, produced more colonies in soft agar, and formed larger tumor upon xenograft injection than the ATF3+/+ counterparts. Importantly, xenograft tumors derived from ATF3-/- cells showed more phospho-histone H3 and less cleaved caspase 3 staining, suggesting that increased proliferation and decreased apoptosis contribute to the enhanced growth of ATF3-/- tumors. ATF3-/- cells, either with or without Ras transformation, had increased Rb phosphorylation and higher levels of various cyclins. Significantly, ATF3 bound to the cyclin D1 promoter and repressed its transcription. Taken together, these results indicate that ATF3 suppresses Ras-mediated tumorigenesis of mouse fibroblasts, at least partially, through promoting apoptosis and cell cycle arrest. The signaling pathways mediating ATF3 induction are not well studied. We demonstrate that p38 signaling pathway is involved in ATF3 induction by stress signals. Ectopic expression of constitutively active MKK6 indicated that p38 pathway was sufficient to induce the expression of ATF3. Inhibition of the pathway either by inhibitor or dominant negative molecule indicated that p38 pathway was necessary for anisomycin, a potent activator of MAPKs, to induce ATF3. In addition, the regulation was at least in part at the transcription level. Interestingly, both ERK and JNK pathways were neither necessary nor sufficient to induce ATF3 in the stress model under examination. Analysis of caspase 3 activation indicated a pro-apoptotic role of p38 pathway and the induction of ATF3 by p38 contributes to the apoptotic effect mediated by p38. Therefore, p38 pathway plays a critical role in the induction of ATF3 by stress signals and ATF3 is a functional downstream target of p38 to mediate the apoptotic effect.
Tsonwin Hai (Advisor)
173 p.
Biology, Molecular
ATF3; tumorigenesis; MAPKs; diabetes; stroma-cancer interaction

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Citations

  • Lu, D. (2006). ATF3, a stress-inducible gene: function and regulation [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1155740569

    APA Style (7th edition)

  • Lu, Dan. ATF3, a stress-inducible gene: function and regulation. 2006. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1155740569.

    MLA Style (8th edition)

  • Lu, Dan. "ATF3, a stress-inducible gene: function and regulation." Doctoral dissertation, Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=osu1155740569

    Chicago Manual of Style (17th edition)

osu1155740569
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© 2006, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.