One of explanations might be that tumor microenvironment is enriched with inflammatory cells accumulating extremely hydrophobic compounds, such as bodily dioxin, a high-affinity ligand for the Ah receptor (AhR). However, the AhR/dioxin/AIP/HSP90 transcriptional complex formed predominantly activates genes encoding pro-inflammatory and malignancy-linked cytokines and cellular factors, as those genes contain more DRE binding sites in their regulatory region than CYP1A1 gene does. So, due to the lack of supporting de novo synthesis, CYP1A1 content in malignant cells goes down.
Certain non cellular high affinity AhR ligands (such as TCDD) are known to decrease AhR levels upon treatment of cells. Therefore, it is intriguing to hypothesize that accumulation of certain "hydrophobic" cellular molecules in tumor cells contributes to increases in AhR levels. Because factors that up-regulate levels of AhR in normal and cancer cells remain largely unknown, other possibilities need to be considered.
Dear Divaker Choubey,
What allowed us hypotesize about "self-induction" by app. 10(-10) M dioxin of AhR/AIP/HSP90 complex was that the following number of new active DREs in 5’-flanking region of human genes was detected: one in AHR (plus three reliable DREs were revealed by SITECON within human AHR gene downstream of the TSS), five in AIP, eight in HSP90AA1, and three in HSP90AB1. The most of newly and previously predicted DREs were found to be conservative in mammals. For more information, please find the paper attached.
Best wishes,
Ilya Tsyrlov
Technical Report DETECTION OF NEW POTENTIALLY ACTIVE DRE SITES IN REGULATORY ...
AhR works through dimerization with ARNT. But also "HIF 1 alpha" acts with dimerization with ARNT (HIF 1 beta). Because cancer cells in hypoxic environment are characterized by a great "HIF 1 alpha" activity, may be that in this condition ARNT is little available for other cellular pathways ?
In particular for the dimerization with AhR .
There is also evidence that ARNT may be directly in connection with growth factors (in the scheme taken from the attached publication)
I am a "surgical pathologist" and I apologize if I'm intruding asking a question. Thanks
Involvement of aryl hydrocarbon receptor nuclear translocator in EGF-induced c-Jun/Sp1 mediated gene expression
Background
EGFR activation is not only important in the regulation of cell proliferation and tumorigenesis through mediating genes expression but is expressed at high levels in a variety of human tumors and has been associated with poor prognosis and lower survival rate. Thus, to identify the factors which participate in the EGF-induced gene expression, resulting in tumorigenesis could improve our knowledge and application in the cancer therapy. One of the factors we first identified in EGF-activated signal pathways is aryl hydrocarbon receptor nuclear translocator (ARNT). ARNT has long been deemed as a general partner to HIF-1α in hypoxia in mediating tumor growth. In addition to its function which has been largely discussed under hypoxia and the stimulation of xenobiotics, less is known about its role in growth factor action. In this study, we clarify the role of ARNT in EGF-induced gene expression which may participate in the process of tumorigenesis.
Results
In order to study whether EGF produces effects on the activation of ARNT, we treated cervical cancer cells with EGF and then the expression of ARNT was detected. We found that EGF induced the phosphorylation and nuclear accumulation of ARNT. EGF also enhanced the association of ARNT with c-Jun/Sp1 complex. Hence, the c-Jun/ARNT/Sp1 complex bound to Sp1 site of genes, such as 12(S)-lipoxygenase and p21WAF1/CIP1 to induce gene expression. EGF induced promoter activity and the mRNA level of 12(S)-lipoxygenase and p21WAF1/CIP1 as well as the association between c-Jun and Sp1 were reduced by ARNT knockdown. Our results reveal a novel mechanism by which ARNT acts as a modulator to bridge the c-Jun/Sp1 interaction and plays a role in EGF-mediated c-Jun/Sp1-dependent gene expression under normoxic conditions. These results are also consistent with our previous report that ARNT/c-Jun complex also mediates EGF-induced cyclooxygenase-2 gene expression. Consistently, cyclooxygenase-2 and ARNT were cohorts present distinctively in clinical speciments of human cervical squamous cell carcinoma.
Conclusion
As shown in Fig. a, ARNT mediates gene expression by recruiting transcription factors c-Jun and Sp1 upon growth factor stimulation and thus activate specific gene expression. In our study we revealed that ARNT, in addition to response to hypoxia and xenobiotics, mediates the activation of growth factor signaling in normoxia (Fig. b). This broadens the role that ARNT plays in physiological and pathophysiological functions.
http://www.ncbi.nlm.nih.gov/pubmed/20508969
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