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Complex Regulation Of Neurofibromatosis Type I Exon 23a Inclusion By The CUG-BP AND ETR-3-LIKE Factors (CELF) And Muscleblind-Like (MBNL) Proteins

Fleming, Victoria Amber

Abstract Details

2012, Doctor of Philosophy, Case Western Reserve University, Genetics.

The human genome contains a relatively small number of genes compared to the complexity and abundance of protein products that are generated from it, so biological mechanisms must be in place to create protein diversity. One of the major mechanisms for regulating gene expression and creating proteomic diversity is alternative splicing, which allows multiple protein products to be generated from a single gene, by selectively including or excluding particular exons in the mature mRNA messages. Our understanding of the mechanisms which regulate alternative splicing has been greatly expanded in recent years, but there is still much to be learned.

Complex control is a common theme for alternative exons, as often there are many protein factors and other regulatory processes responsible for the decision of whether a particular alternative exon will be included or skipped in a particular tissue or at a particular developmental stage. Our laboratory has identified an alternatively spliced exon, which is under complex splicing control: neurofibromatosis type I (NF1) exon 23a.

NF1 exon 23a lies within the best-characterized functional domain of the NF1 protein, the GAP-related domain (GRD). The GRD allows the NF1 protein to act as a negative regulator of the oncogene, Ras by facilitating the conversion of the active GTP-bound form of Ras to the inactive GDP-bound form. The protein isoform that contains exon 23a is about ten times less efficient at facilitating this conversion than its counterpart in which the exon is excluded.

NF1 exon 23a is regulated by at least four different protein families: the Hu proteins, the TIA-1 and TIAR proteins, the CUG-BP and ETR-3-Like Factors (CELF proteins) and the Muscleblind-like (MBNL proteins). My work has expanded our understanding of this complex regulation by adding the CELF and MBNL proteins to the list of RNA binding proteins, which regulate this important alternative splicing event. Additionally, my studies have established NF1 exon 23a as one of a few pre-mRNA targets of antagonistic CELF and MBNL protein-mediated splicing regulation. My in vitro experiments show that MBNL and CELF proteins regulate this exon by binding to UG-rich elements in the intron upstream of the exon.

Hua Lou, Ph.D. (Advisor)
Guangbin Luo, Ph.D. (Committee Chair)
Helen Salz, Ph.D. (Committee Member)
Andrea Ladd, Ph.D. (Committee Member)
125 p.

Recommended Citations

Citations

  • Fleming, V. A. (2012). Complex Regulation Of Neurofibromatosis Type I Exon 23a Inclusion By The CUG-BP AND ETR-3-LIKE Factors (CELF) And Muscleblind-Like (MBNL) Proteins [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1333490345

    APA Style (7th edition)

  • Fleming, Victoria. Complex Regulation Of Neurofibromatosis Type I Exon 23a Inclusion By The CUG-BP AND ETR-3-LIKE Factors (CELF) And Muscleblind-Like (MBNL) Proteins. 2012. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1333490345.

    MLA Style (8th edition)

  • Fleming, Victoria. "Complex Regulation Of Neurofibromatosis Type I Exon 23a Inclusion By The CUG-BP AND ETR-3-LIKE Factors (CELF) And Muscleblind-Like (MBNL) Proteins." Doctoral dissertation, Case Western Reserve University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=case1333490345

    Chicago Manual of Style (17th edition)