Department of Chemistry and Chemistry Institute of Functional Materials, Pusan National University, Busan 609-735, Republic of Korea.
Department of Chemistry and Chemistry Institute of Functional Materials, Pusan National University, Busan 609-735, Republic of Korea.
Toxicol Lett. 2014 Apr 7;226(1):6-13. doi: 10.1016/j.toxlet.2014.01.032. Epub 2014 Jan 31.
The estrogen receptor (ER) and aryl hydrocarbon receptor (AhR) are ligand-activated transcription factors involved in estrogen or xenobiotic exposure, whereas the 90-kDa heat shock protein (HSP90), which is a ubiquitously expressed molecular chaperone, is involved in the signal transduction process. Although the interactions between these pathways have been under investigation, the mechanisms are unclear and the potential role of HSP90 in these interactions has not been reported. The results of goldfish primary hepatocytes showed that exposure to PCB77 and 17β-estradiol (E2) alone induced significant protein expression of cytochrome P450 1A (CYP1A) and vitellogenin (VTG), respectively. On the other hand, the combined exposure to PCB77 and E2 led to the reduction of CYP1A and VTG compared to the single treatments. Although the AhRs and ERs were naturally induced during the co-treatment, the total amount of HSP90 binding to the receptors was not changed. Furthermore, while the HSP90 chaperon activity was blocked by the specific inhibitor (geldanamycin), reciprocal inhibition between AhR and ER pathways was not observed. These findings indicate a potential role of HSP90 where competition between AhR and ER for binding to HSP90 can occur and cause reciprocal inhibition.
雌激素受体（ER）和芳香烃受体（AhR）是配体激活的转录因子，参与雌激素或外源性物质暴露，而 90kDa 热休克蛋白（HSP90）是一种广泛表达的分子伴侣，参与信号转导过程。虽然这些途径之间的相互作用一直在研究中，但机制尚不清楚，HSP90 在这些相互作用中的潜在作用尚未报道。金鱼原代肝细胞的结果表明，单独暴露于 PCB77 和 17β-雌二醇（E2）分别诱导细胞色素 P450 1A（CYP1A）和卵黄蛋白原（VTG）的显著蛋白表达。另一方面，与单一处理相比，PCB77 和 E2 的联合暴露导致 CYP1A 和 VTG 的减少。尽管 AhRs 和 ERs 在共同处理期间自然诱导，但与受体结合的 HSP90 的总量没有变化。此外，虽然 HSP90 伴侣活性被特异性抑制剂（格尔德霉素）阻断，但 AhR 和 ER 途径之间没有观察到相互抑制。这些发现表明 HSP90 的潜在作用，即 AhR 和 ER 之间可能发生竞争结合 HSP90，并导致相互抑制。
