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  • Ulfhammer, Erik, 1974, et al. (author)
  • Dependence of Proximal GC Boxes and Binding Transcription Factors in the Regulation of Basal and Valproic Acid-Induced Expression of t-PA.
  • 2016
  • In: International journal of vascular medicine. - : Hindawi Limited. - 2090-2824 .- 2090-2832. ; 2016
  • Journal article (peer-reviewed)abstract
    • Objective. Endothelial tissue-type plasminogen activator (t-PA) release is a pivotal response to protect the circulation from occluding thrombosis. We have shown that the t-PA gene is epigenetically regulated and greatly induced by the histone deacetylase (HDAC) inhibitor valproic acid (VPA). We now investigated involvement of known t-PA promoter regulatory elements and evaluated dependence of potential interacting transcription factors/cofactors. Methods. A reporter vector with an insert, separately mutated at either the t-PA promoter CRE or GC box II or GC box III elements, was transfected into HT-1080 and HUVECs and challenged with VPA. HUVECs were targeted with siRNA against histone acetyl transferases (HAT) and selected transcription factors from the Sp/KLF family. Results. An intact VPA-response was observed with CRE mutated constructs, whereas mutation of GC boxes II and III reduced the magnitude of the induction by 54 and 79% in HT-1080 and 49 and 50% in HUVECs, respectively. An attenuated induction of t-PA mRNA was observed after Sp2, Sp4, and KLF5 depletion. KLF2 and p300 (HAT) were identified as positive regulators of basal t-PA expression and Sp4 and KLF9 as repressors. Conclusion. VPA-induced t-PA expression is dependent on the proximal GC boxes in the t-PA promoter and may involve interactions with Sp2, Sp4, and KLF5.
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Type of publication
journal article (1)
Type of content
peer-reviewed (1)
Author/Editor
Jern, Sverker, 1954 (1)
Carlsson, Lena M S, ... (1)
Bergh, Niklas, 1979 (1)
Ulfhammer, Erik, 197 ... (1)
Larsson, Pia, 1978 (1)
Magnusson, Mia, 1979 (1)
University
University of Gothenburg (1)
Language
English (1)
Research subject (UKÄ/SCB)
Medical and Health Sciences (1)
Year

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