Graduation Year
2021
Document Type
Thesis
Degree
M.S.
Degree Name
Master of Science (M.S.)
Degree Granting Department
Biology (Cell Biology, Microbiology, Molecular Biology)
Major Professor
Sandy Westerheide, Ph.D.
Committee Member
Margaret Park, Ph.D., M.S.
Committee Member
Marcus Cooke, Ph.D.
Keywords
CPEB2, translation, angiogenesis, hypoxic stress response
Abstract
Chronic pulmonary hypoxia commonly results in the sustained expression of HIF1 (hypoxia inducible factor 1), a heterodimeric transcription factor, that, if unrestrained, can result in dramatic vasculature remodeling, pulmonary arterial hypertension, and right-sided heart failure. Together, these pulmonary disorders cost approximately $100 billion annually to treat due to the limited therapeutic targets designed to inhibit HIF1 expression. In this study, we introduce a translational regulator of HIF1 expression, known as Cytosolic polyadenylation element binding proteins 2 (CPEB2). Our lab has previously demonstrated in cancer cells that alternatively spliced isoforms of CPEB2 regulate the translation of the HIF1 oxygen-dependent subunit, HIF1α, in opposing fashions: the CPEB2A isoform represses its translation, while the CPEB2B isoform activates its translation. Although it is well established that during hypoxia, HIF1α levels are initially upregulated due to a decrease in proteasomal degradation, we hypothesized that during prolonged, or chronic, hypoxia, the expression of HIF1α is maintained through a stress-induced translational mechanism, likely alongside a decrease in proteolytic activity meant to stabilize HIF1α protein. Here we have demonstrated that targeting the CPEB2B splice isoform inhibited the translation of nascent HIF1α protein during chronic hypoxia, but not during acute hypoxia exposure. Moreover, we characterized how CPEB2A and B expression impacts vasculature remodeling in a 3D angiogenic cell model. These findings provide evidence that this splicing event could act as a therapeutic target for treating chronic hypoxia-related pulmonary diseases and diseases that present with dysregulated HIF1 expression.
Scholar Commons Citation
Mayo, Emily M., "Cytoplasmic Polyadenylation Element Binding Protein 2 Alternative Splicing Regulates HIF1α During Chronic Hypoxia" (2021). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/9182
