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Elucidating Mechanisms of Alternative Splicing in Cancer and Cellular Stress

Montes Serey, Matias Ignacio
http://orcid.org/0000-0003-3637-6379
http://rave.ohiolink.edu/etdc/view?acc_num=osu1626990418122016

Abstract Details

2021, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Alternative splicing of the pre-mRNA is an essential post-transcriptional process in eukaryotes that generates multiple protein isoforms from a single gene. However, this process can be disrupted by mutations leading to several diseases including cancer. One such example is the oncogene and negative regulator of p53 Mouse Double Minute 2 homolog (MDM2), which undergoes alternative splicing to produce a splice isoform that has novel implications in cancer development. MDM2-Alt1 comprised of coding exons 3 and 12, is highly expressed in several cancers including those of the breast, liposarcomas, high-grade gliomas and rhabdomyosarcomas (RMS), and can be induced by genotoxic stress. Another good example of cancer-related aberrant alternative splicing, is the insulin receptor gene (INSR), comprised of 22 exons, and that skipping of the exon 11 allows the production of the IR-A splice isoform. Overexpression of the IR-A isoform compared to the full-length IR-B isoform, has been reported in several cancers including RMS, osteosarcoma, breast cancer, prostate cancer and hepatocellular carcinoma. Understanding of the splicing mechanisms of these two genes is crucial to improve current cancer therapies. In this work we report that SRSF2 positively regulates the alternative splicing of MDM2 and that its binding to the exon 11 can be modulated to generate novel mouse model for cancer studies. Furthermore, we show a novel and unique regulatory mechanism of splicing wherein a nuclear microRNA, miR-29b, influences the alternative splicing of MDM2 by directly binding to the MDM2 pre-mRNA. We show that miR-29b is downregulated by genotoxic stress, a similar characteristic of cancer cells. Finally, we study the usage of antisense oligonucleotides (ASOs) as cancer therapies, by blocking the binding of the CUG-BP1 (CUG Binding Protein 1) splicing factor with an ASO, we promote the alternative splicing of the IR-B isoform which decreases cell proliferation and angiogenesis. Moreover, modulation of the MBNL1 (Muscleblind Like 1) intronic splicing enhancer in the intron 11 of the INSR, set the foundation for a novel mouse model to study this aberrant alternative splicing. Overall, our study underscores the importance of understanding alternative splicing in cancer research, moreover, it expands the knowledge regarding the complex splicing mechanisms involved in disease and finally set the foundations for the design of novel and effective splice-switching cancer therapies.
Dawn Chandler (Advisor)
Guramrit Singh (Committee Member)
Kotaro Nakanishi (Committee Member)
Anita Hopper (Committee Member)
182 p.
Biochemistry; Cellular Biology; Molecular Biology
Alternative Splicing; MDM2; miRNAs; INSR; Genotoxic Stress; Rhabdomyosarcoma; miR-29b

Recommended Citations

Citations

  • Montes Serey, M. I. (2021). Elucidating Mechanisms of Alternative Splicing in Cancer and Cellular Stress [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1626990418122016

    APA Style (7th edition)

  • Montes Serey, Matias. Elucidating Mechanisms of Alternative Splicing in Cancer and Cellular Stress. 2021. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1626990418122016.

    MLA Style (8th edition)

  • Montes Serey, Matias. "Elucidating Mechanisms of Alternative Splicing in Cancer and Cellular Stress." Doctoral dissertation, Ohio State University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=osu1626990418122016

    Chicago Manual of Style (17th edition)

osu1626990418122016
99
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This open access ETD is published by The Ohio State University and OhioLINK.
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