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Regulation of Tumorigenic Spliced Isoforms in Cancer

Tapia-Santos, Aixa S.
http://rave.ohiolink.edu/etdc/view?acc_num=osu1300939562

Abstract Details

2011, Master of Science, Ohio State University, Molecular, Cellular and Developmental Biology.
MDM2 negatively regulates the tumor suppressor protein p53 by blocking its transcriptional activation domain and targeting p53 for proteosomal degradation. Upon induction of specific DNA damage and in cancer the MDM2 transcript undergoes drastic exclusion of its internal exons through the process of alternative splicing. This damage induced alternative splicing results in the generation of the most common alternative spliced form identified in human cancers, MDM2-ALT1. As opposed to full length MDM2, MDM2-ALT1 lacks the p53 binding domain which renders this protein isoform incapable of an interaction with the tumor suppressor. However, our lab and others have shown that MDM2-ALT1 is capable of binding full length MDM2 and to sequester it to the cytoplasm. This MDM2-MDM2-ALT1 interaction inhibits the negative regulation exerted by MDM2 over p53. Therefore, MDM2-ALT1 through its interaction with MDM2, mediates a protective program in which p53 is stabilized and cell cycle arrest, DNA repair and/or apoptosis is induced as a consequence. Because the observed role of MDM2-ALT1 in promoting cell proliferation inhibition is inconsistent to its extensive detection in human cancers, we decided to investigate the regulation behind the alternative splicing of MDM2 and also to determine its role in tumorigenesis. We have identified positive and negative exonic splicing regulators of MDM2 using a system of MDM2 minigenes that upon induction of DNA damage parallel the alternative splicing events that take place in a cancer cellular context in which the generation of MDM2-ALT1 is characteristic. To identify the role of MDM2-ALT1 in tumorigenesis we have generated an in vivo mouse model in which the expression of MDM2-ALT1 is restricted to B cells. We report that mice expressing the MDM2-ALT1 transgene show a significant prevalence in the emergence of degenerative joint disease, an inflammatory disorder associated to the clonal expansion of B cells. Further characterization of the expression of MDM2-ALT1 in B cells using our mouse model is still to prove its usefulness in elucidating the role of MDM2-ALT1 in tumorigenesis.
Dawn Chandler (Advisor)
Peter Houghton (Committee Member)
Santiago Partida-Sanchez (Committee Member)
104 p.
Molecular Biology
MDM2; alternative splicing; SC35; SF2/ASF

Recommended Citations

Citations

  • Tapia-Santos, A. S. (2011). Regulation of Tumorigenic Spliced Isoforms in Cancer [Master's thesis, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1300939562

    APA Style (7th edition)

  • Tapia-Santos, Aixa. Regulation of Tumorigenic Spliced Isoforms in Cancer. 2011. Ohio State University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1300939562.

    MLA Style (8th edition)

  • Tapia-Santos, Aixa. "Regulation of Tumorigenic Spliced Isoforms in Cancer." Master's thesis, Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1300939562

    Chicago Manual of Style (17th edition)

osu1300939562
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© 2011, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.