Biochem. J. (2009) 419
(419–425) (Printed in Great Britain)
Role of aryl hydrocarbon receptor in modulation of the expression of the hypoxia marker carbonic anhydrase IX
Martina TAKACOVA*1, Tereza HOLOTNAKOVA*1, Jan VONDRACEK†, Miroslav MACHALA‡, Katerina PENCIKOVA‡, Katarina GRADIN§, Lorenz POELLINGER§, Jaromir PASTOREK*, Silvia PASTOREKOVA* and Juraj KOPACEK*2
*Institute of Virology, Centre of Molecular Medicine, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovak Republic, †Department of Cytokinetics, Institute of Biophysics, AS CR, Kralovopolska 135, 612 65 Brno, Czech Republic, ‡Department of Chemistry and Toxicology, Veterinary Research Institute, Hudcova 70, 621 00 Brno, Czech Republic, and §Department of Cell and Molecular Biology, Karolinska Institute, S-171 77 Stockholm, Sweden
Tumour-associated expression of CA IX (carbonic anhydrase IX) is to a major extent regulated by HIF-1 (hypoxia-inducible factor-1) which is important for transcriptional activation and consists of the oxygen-regulated subunit HIF-1α and the partner factor ARNT [AhR (aryl hydrocarbon receptor) nuclear translocator]. We have previously observed that HIF-1α competes with the AhR for interaction with ARNT under conditions when both conditionally regulated factors are activated. We have therefore investigated whether TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin)-induced activation of the AhR pathway might interfere with CA IX expression. The results from the present study suggest that TCDD treatment reduces hypoxic induction of both CA IX mRNA and protein expression. Moreover, the transcriptional activity of the CA9 promoter was significantly reduced by expression of CAAhR (constitutively active AhR), which activates transcription in a ligand-independent manner. Finally, we found that ARNT is critical for both hypoxic induction and the TCDD-mediated inhibition of CA9 expression.
Key words: aryl hydrocarbon receptor (AhR), carbonic anhydrase IX, dioxin, hypoxia, nuclear translocator of AhR, transcriptional regulation.
Abbreviations used: AhR, aryl hydrocarbon receptor; ARNT, AhR nuclear translocator; bHLH, basic helix–loop–helix; CA IX, carbonic anhydrase IX protein; CA9, CA IX gene; CAAhR, constitutively active AhR; ChIP, chromatin immunoprecipitation; HIF, hypoxia-inducible factor; HRE, hypoxia response element; Hsp90, heat-shock protein 90; PAS, Per/ARNT/Sim; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; XRE, xenobiotic response element.
1These authors contributed equally to this work.
2To whom correspondence should be addressed (email virukopa@savba.sk).
Received 15 September 2008/16 January 2009; accepted 20 January 2009
Published as BJ Immediate Publication 20 January 2009, doi:10.1042/BJ20080952
© The Authors Journal compilation © 2009 Biochemical Society
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