Tubedown in the regulation of the P53 tumor suppressor pathway

Davidson, Cassandra (2019) Tubedown in the regulation of the P53 tumor suppressor pathway. Masters thesis, Memorial University of Newfoundland.

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Abstract

Tubedown (TBDN) was initially discovered as a developmentally regulated protein, highly expressed during embryogenesis in neuroectodermal and mesenchymal lineages. TBDN is the regulatory subunit of the Nα-terminal acetyltransferase complex NatA, in conjunction with catalytic subunit Arrest-defective-1 protein (ARD1). In adulthood and aging, TBDN is involved in the regulation of retinal vascular permeability. It has been shown that TBDN is highly expressed in primitive bone tumors of mesenchymal and neuroectodermal origin, such as osteosarcoma (OS) and Ewing’s sarcoma (EWS). Previous work in our lab suggests: TBDN is required for tumor cell growth via regulation of p53 tumor suppression; and, aged mice overexpressing TBDN under the inducible endothelial/mesenchymal Tie2 promoter develop tumors in specific tissues. The focus of this study is to examine the role of TBDN in Ewing’s sarcoma and during aging in mice, specifically in relation to p53 tumor suppression, in order to better understand the role of Nα-terminal acetyltransferases in cancer and aging. The role of TBDN and ARD1 in the regulation of p53 levels and cell proliferation in Ewing’s sarcoma cells in vitro was studied using an siRNA knockdown approach. The role of TBDN during aging was studied in a bi-transgenic HHrtTAXK-TRE/HA-TBDN mouse model overexpressing TBDN under the Dox-inducible endothelial/mesenchymal Tie2 promoter. Ewing’s sarcoma cells knocked down for either TBDN or ARD1 expression showed upregulated p53 expression and reduced cell proliferation when compared to controls. The analysis of tumors collected from bi-transgenic HHrtTAXK-TRE/HA-TBDN aged mice overexpressing TBDN under the Tie2 promoter showed overexpression of TBDN in the cells and blood vessels of the tumors. TBDN overexpression in mice during aging resulted in suppressed p53 expression in comparison to control mice. My results suggest that TBDN dysregulation of the tumor suppressor p53 could be involved in facilitating tumor formation.

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