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Phosphotyrosine-mediated signal transduction pathways essential for RET/PTC1-induced tumor formation

Buckwalter, Tara Lynne Furminger
http://rave.ohiolink.edu/etdc/view?acc_num=osu970163275

Abstract Details

2000, Doctor of Philosophy, Ohio State University, Biochemistry.
The PTC1 oncogene is a rearranged form of the RET proto-oncogene detected in human papillary thyroid carcinomas (PCs). The tumorigenicity of PTC1 in thyroid tumors has been demonstrated in transgenic mice with thyroid-targeted expression of PTC1 using the bovine thyroglobulin (Tg) promoter. Previous signal transduction studies using cultured cells suggest that the phosphotyrosine residues (pY), pY294, pY404, and pY451, play important roles in PTC1-induced transformation via signaling pathways mediated by signaling molecules Grb10, PLCg, or Enigma and Shc, respectively. In this study, transgenic mice expressing thyroid-targeted PTC1 mutants, abolishing the signaling pathways mediated by one or three of these three pY, were generated to investigate which signaling pathways are essential for PTC1-induced thyroid tumor formation in vivo. Furthermore, other studies have shown PTC1-induced activation of the ras/MAPK pathway. Thus, the role of MAPK activation towards thyroid tumor formation in these transgenic mice was also evaluated. Site-directed mutagenesis generated three single mutants of PTC1-Y294F, PTC1-Y404F, or PTC1-Y451F, as well as a triple mutant PTC1-3Y/F carrying mutations Y294F, Y404F, and Y451F. Tyrosine kinase activity appears to be essential for PTC1-mediated signal transduction as the PTC1-3Y/F mutant had an absence of tyrosine phosphorylation in cell culture and the Tg-PTC1-3Y/F transgenic group had 0% tumor formation in vivo. As Tg-PTC1-Y(294, 404, or 451)F transgenic mice thyroids had a decrease in the rate of tumor formation compared to the Tg-PTC1 transgenic mice (6, 40, or 31% vs. 100%, respectively), signal transduction pathways mediated by pY294, pY404 and pY451 do appear to play a role in PTC1-induced thyroid tumor progression, with apparently the most significant contribution from the pY294-mediated signaling pathway (Grb10) and the least impact from the pY404-mediated pathway (PLCg). However, as thyroid tumors were still observed in each single Y/F mutant group, it appears that signaling pathways mediated by one of these three pY can be compensated by alternative pathways, leading to tumor formation. Lastly, intra- and inter-line variations in the histological grading suggest that the onset, duration and overall level of transgene expression may play an important role in PTC1-induced tumor formation.
Sissy Jhiang (Advisor)
thyroid tumor; phosphotyrosine; RET/PTC1

Recommended Citations

Citations

  • Buckwalter, T. L. F. (2000). Phosphotyrosine-mediated signal transduction pathways essential for RET/PTC1-induced tumor formation [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu970163275

    APA Style (7th edition)

  • Buckwalter, Tara. Phosphotyrosine-mediated signal transduction pathways essential for RET/PTC1-induced tumor formation. 2000. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu970163275.

    MLA Style (8th edition)

  • Buckwalter, Tara. "Phosphotyrosine-mediated signal transduction pathways essential for RET/PTC1-induced tumor formation." Doctoral dissertation, Ohio State University, 2000. http://rave.ohiolink.edu/etdc/view?acc_num=osu970163275

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.