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Role of Ets-2 in lymphocyte development, function, and survival

Fisher, Ian Bradford
http://rave.ohiolink.edu/etdc/view?acc_num=osu1101154514

Abstract Details

2004, Doctor of Philosophy, Ohio State University, Molecular, Cellular, and Developmental Biology.
Ets transcription factors have been implicated in the development, regulation, and survival of numerous hematopoietic derived cells, including B and T-lymphocytes. E26 avian leukemia oncogene-2 (Ets-2) is an Ets family member transcription factor. Strong expression of Ets-2 is observed in developing thymocytes from the DN1 stage and in B-cells from the pro-B stage. A conserved sequence within the Ets-2 pointed domain amino acids 69 to 73 PLLTP is able to interact with the Map kinase ERK. Threonine seventy-two is phosphorylated by ERK1, and permits transactivation by Ets-2. Mutation of this residue from a threonine to an alanine, Ets-2 T72A, abrogates Ras mediated transactivation of Ets-2. Based on this evidence, we hypothesized that Ets-2 was important in T- and B-cell development, activation, and function. To test this hypothesis we analyzed Ets-2 activation in T-cell lines, and created two transgenic mice lines that express Ets-2 T72A in either developing T-cells or B-cells. Transactivation of Ets-2 can be induced by both Ras activation and by phorbol 12-myristate 13-acetate and ionomycin stimulation in the Jurkat T-cell line. In-vitro analysis of Ets-2 activation by ionomycin results in a rapid, but transient Ets-2 band shift as evidenced by western blot analysis of protein extracts from thymocytes. Transgenic mice that over-express Ets-2 T72A in the thymus displayed a dramatic reduction in thymus size associated with hypocellularity. This reduction was associated with a partial developmental block at the double negative 2 and double negative 3 stage of development, a twenty-fold increase in c-Kit+ expression, and a five-fold increase the CD5low population. Further, thymocytes from the transgenic mice have increased apoptosis both in-vitro and in-vivo compared to non-transgenic littermates. Transgenic mice that over-express Ets-2 T72A in B-lymphocytes revealed a loss of the B220Hi population of B-cells in the bone marrow. This population consists of mature B-cells that are characterized to be IgM+, IgD+ and Cd49d+ mature lymphocytes. Analysis of transgenic Ets-2 T72A B-cells in other secondary lymph organs did not reveal any defects. This dissertation demonstrates that Ets-2 is an important target in lymphocyte development and function. It is involved in T-cell development and survival and in establishment of mature bone marrow B-cells.
Natarajan Muthusamy (Advisor)
185 p.
Biology, Cell
Ets transcription factors; Ets-2; Thymus; Thymocytes; T-lymphocytes; Bone marrow; Spleen; B-lymphocytes; Ras; MapK; Transgenic Mice

Recommended Citations

Citations

  • Fisher, I. B. (2004). Role of Ets-2 in lymphocyte development, function, and survival [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1101154514

    APA Style (7th edition)

  • Fisher, Ian. Role of Ets-2 in lymphocyte development, function, and survival. 2004. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1101154514.

    MLA Style (8th edition)

  • Fisher, Ian. "Role of Ets-2 in lymphocyte development, function, and survival." Doctoral dissertation, Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1101154514

    Chicago Manual of Style (17th edition)

osu1101154514
852
© 2004, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.