Both AhR and HIF1-alpha form heterodimers with ARNT (HIF1-beta).
There are many papers that indicate a possible use of drugs that determine an hyperactivity of AhR in the treatment of various cancers, but I never saw a link with a decreased activity of HIF1-alpha.
https://www.researchgate.net/post/Could_HIF1B_which_constitutes_together_with_HIF1-alpha_the_HIF1_heterodimer_be_one_of_the_links_between_mTOR_and_the_estrogen_receptor
Hi Maurizio,
You might find all information about a cross talk between ARNT-requiring pathways mediated by AhR and HIF1 from research data of G. Perdew of PennState CAS, J. Isaacs of Med University SC, and I. Pongratz, L. Poellinger of Karolinska Institutet. Also, in 2001 M. Nie et al published a paper “Interactions between aryl hydrocarbon receptor (AhR) and hypoxia signaling pathways” (Environmental Toxicol Pharmacol 10:17–27, 2001), where they presumed that since both the AhR and hypoxia transcriptional pathways require ARNT, some of the effects of TCDD and similar types of ligands could be explained by interaction between the AhR and hypoxia pathways involving ARNT. Their studies tested the hypothesis that there is cross talk between AhR- and HIF-1-mediated transcription pathways. It was shown that TCDD significantly reduced the hypoxia-mediated reporter gene activity in B-1 cells. Reciprocally, the hypoxia response inducers desferrioxamine or CoCl2 inhibited AhR-mediated CYP1A1 enzyme activity in B-1 and Hepa 1 cells, and the AhR-mediated luciferase reporter gene activity in H1L1.1c2 cells. The interaction between the AhR- and HIF-1-mediated transcription can be attributed to changes in DNA binding activities. TCDD-induced protein binding to dioxin responsive element (DRE) was diminished by desferrioxamine, and TCDD reduced the binding activity to HIF-1 binding site in desferrioxamine-treated Hepa 1 cells. This mutual repression may provide an underlying mechanism for many TCDD-induced toxic responses.
My team has used different approach to that point. Thus we performed a computational SITECON search for dioxin responsive elements (DREs) in genes of proteins comprising the Ah receptor (AhR) cytosolic core complex. (E. Nedosekina et al., Organohalogen Compounds, volume 69, pp.1889-1894, 2007). Eventually, the following number of new DREs in 5’-flanking region was detected by SITECON: one in AHR gene, five in XAP2, eight in HSP90AA1, and three in HSP90AB1 genes. Additional DREs found in genes of AhR and AhR cytosolic complex members would shed a light on potential mechanisms of expression, stoichiomentry of unliganded AhR core complex, and its degradation vs biosynthesis dynamics resulted from treatment of U937 cells with the AhR most potent ligand, 2,3,7,8-TCDD. To your very question, we did not find any DRE in regulatory regions of gene encoding HIF-1 (unpublished data). So, in contrast to the data of Nie et al (2001), interaction between the AhR- and HIF-1-mediated transcription can NOT be attributed to changes in DNA binding activities, and has to be explained by another mechanism.
Best wishes,
Ilya
Yes, in Lee et al., we found several hundred hypoxia responsive genes are disrupted by TCDD treatment in Hep3B cells.
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