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The aryl hydrocarbon receptor (AhR) is a cytosolic, ligand-activated transcription factor that plays a role in polycyclic aromatic hydrocarbon (PAH)-induced carcinogenesis.

Figure 1    Three examples of polycyclic aromatic hydrocarbons (PAHs).

Tobacco smoke contains PAHs, which activate AhR signaling leading to increased transcription of CYP1A1 and CYP1B1, which encode proteins that convert the PAHs into mutagens.

It is suspected that AhR-dependent expression of CYP1A1 and CYP1B1 may be affected by the status of the p53 proto-oncogene. To evaluate this, two experiments were conducted using the colon carcinoma cell line EB-1, which carries wild-type p53 that is under the control of an inducible metallothionein promoter that exhibits little or no detectable basal activity but sustains high levels of p53 expression following stimulation with ZnCl2.

Experiment 1

EB-1 cells were transfected with a p53-luciferase reporter construct, followed by treatment with varying doses of ZnCl2. The results are shown in Figure 2.

Figure 2    EB-1 p53 luciferase activity at varying ZnCl2 concentrations.

Experiment 2

EB-1 cells transfected with an XRE-luciferase construct (activated AhR binds to XREs in the promoters of CYP1A1 and CYP1B1) are incubated with PAHs. The samples are then dosed with ZnCl2 in the same manner as in experiment 1. The results are shown in Figure 3.

Figure 3    XRE luciferase activity at varying ZnCl2 concentrations for EB-1 cells incubated with PAHs.

Adapted from Kochhar, A. p53 Modulates Hsp90 ATPase Activity and Regulates Aryl Hydrocarbon Receptor Signaling. Cancer Prev Res June 2014 7; 596

In the absence of a ligand, AhR is present in the cytosol in a complex that includes a dimer of the heat shock protein Hsp90. Once a PAH binds to AhR, the complex alters its folding pattern and disassembles, then translocates to the nucleus. What class of protein does Hsp90 most likely belong to?