Transcriptional and Post-Transcriptional Regulation of Thrombospondin-1 Expression: A Computational Model
Fig 6
Low oxygen induces TSP-1 expression by different mechanisms.
(A) TSP-1 protein expression is increased along with decreased oxygen availability. (B) Hypoxia increases the transcriptional activity of TSP-1 gene through the induction of its promoters. (C-D) miR-18a, a TSP-1 targeting miR, is downregulated in hypoxia due to the downregulation of its promoter Myc, and (E) miR processing molecules AGO1 and Dicer. (F) Hypoxia de-suppresses the TSP-1 mRNA that was originally under miR-mediated repression, which contributes to the increase of total translatable TSP-1 mRNA. The ratio of repressed TSP-1 mRNA over free mRNA decreases more than tenfold in the condition of 2% oxygen. (G) Model prediction of a nonlinear behavior in TSP-1 synthesis with respect to oxygen tension. This relationship may be partially contributed by the switch-like nature of cellular oxygen sensing [22, 82, 84]. (B-G) Results are normalized with respect to the normoxic baseline values.