Characterization of promoter 3 of the human thromboxane A receptor gene. A functional AP-1 and octamer motif are required for basal promoter activity.
The TPalpha and TPbeta isoforms of the human thromboxane A(2) receptor ( TP) arise by differential splicing but are under the transcriptional control of two distinct promoters, termed Prm1 and Prm3, respectively (Coyle et al. 2002 Eur J Biochem269, 4058-4073). The aim of the current study was to determine the key factors regulating TPbeta expression by functionally characterizing Prm3, identifying the core promoter and the cis-acting elements regulating basal Prm3 activity. Hence, the ability of Prm3 and a series of Prm3 deleted/mutated subfragments to direct reporter gene expression in human erythroleukemia 92.1.7 and human embryonic kidney 293 cells was investigated. It was established that nucleotides -118 to +1 are critical for core Prm3 activity in both cell types. Furthermore, three distinct regulatory regions comprising of an upstream repressor sequence, located between -404 to -320, and two positive regulatory regions required for efficient basal gene expression, located between -154 to -106 and -50 to +1, were identified within the core Prm3. Deletion and site-directed mutagenesis of consensus Oct-1/2 and AP-1 elements within the latter -154 to -106 and -50 to +1 regions, respectively, substantially reduced Prm3 activity while mutation of both elements abolished Prm3 activity. Electromobility shift and supershift assays confirmed the specificity of nuclear factor binding to the latter Oct-1/2 and AP-1 elements. Moreover, herein it was established that the core AP-1 element mediates phorbol myristic acid-induction of Prm3 activity hence providing a mechanistic explanation of phorbol ester up-regulation of TPbeta mRNA expression.[1]References
- Characterization of promoter 3 of the human thromboxane A receptor gene. A functional AP-1 and octamer motif are required for basal promoter activity. Coyle, A.T., Kinsella, B.T. FEBS J. (2005) [Pubmed]
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