bHLH–PAS proteins in cancer

Bersten, David C.; Sullivan, Adrienne E.; Peet, Daniel J.; Whitelaw, Murray L.

doi:10.1038/nrc3621

Cited by 220 publications

(212 citation statements)

References 178 publications

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“…The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor of the basic region helix-loop-helix-PER/ARNT/SIM homology family (Bersten et al, 2013). AHR was first identified in the early 1970s as the mediator of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD/ dioxin) toxicity (Poland and Knutson, 1982).…”

Section: Introductionmentioning

confidence: 99%

Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation

Hubbard¹,

Murray²,

Perdew³

2015

Drug Metab Dispos

488

432

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The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor recognized for its role in xenobiotic metabolism. The physiologic function of AHR has expanded to include roles in immune regulation, organogenesis, mucosal barrier function, and the cell cycle. These functions are likely dependent upon ligandmediated activation of the receptor. High-affinity ligands of AHR have been classically defined as xenobiotics, such as polychlorinated biphenyls and dioxins. Identification of endogenous AHR ligands is key to understanding the physiologic functions of this enigmatic receptor. Metabolic pathways targeting the amino acid tryptophan and indole can lead to a myriad of metabolites, some of which are AHR ligands. Many of these ligands exhibit species selective preferential binding to AHR. The discovery of specific tryptophan metabolites as AHR ligands may provide insight concerning where AHR is activated in an organism, such as at the site of inflammation and within the intestinal tract.

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Section: Introductionmentioning

confidence: 99%

Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation

Hubbard¹,

Murray²,

Perdew³

2015

Drug Metab Dispos

488

432

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“…In general, these proteins form heterodimers that consist of a signal-induced subunit and an unregulated, ubiquitously expressed subunit (1). A member of the family of bHLH-PAS proteins is the AhR.…”

mentioning

confidence: 99%

A Molecular Mechanism To Switch the Aryl Hydrocarbon Receptor from a Transcription Factor to an E3 Ubiquitin Ligase

Luecke-Johansson

Gralla

Rundqvist

et al. 2017

Molecular and Cellular Biology

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The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is known as a mediator of toxic responses. Recently, it was shown that the AhR has dual functions. Besides being a transcription factor, it also possesses an intrinsic E3 ubiquitin ligase function that targets, e.g., the steroid receptors for proteasomal degradation. The aim of this study was to identify the molecular switch that determines whether the AhR acts as a transcription factor or an E3 ubiquitin ligase. To do this, we used the breast cancer cell line MCF7, which expresses a functional estrogen receptor alpha (ER␣) signaling pathway. Our data suggest that aryl hydrocarbon receptor nuclear translocator (ARNT) plays an important role in the modulation of the dual functions of the AhR. ARNT knockdown dramatically impaired the transcriptional activation properties of the ligand-activated AhR but did not affect its E3 ubiquitin ligase function. The availability of ARNT itself is modulated by another basic helix-loop-helix (bHLH)-Per-ARNT-SIM (PAS) protein, the repressor of AhR function (AhRR). MCF7 cells overexpressing the AhRR showed lower ER␣ protein levels, reduced responsiveness to estradiol, and reduced growth rates. Importantly, when these cells were used to produce estrogendependent xenograft tumors in SCID mice, we also observed lower ER␣ protein levels and a reduced tumor mass, implying a tumor-suppressive-like function of the AhR in MCF7 xenograft tumors.KEYWORDS aryl hydrocarbon receptor, molecular switch, E3 ubiquitin ligase, transcription factor, aryl hydrocarbon receptor nuclear translocator, aryl hydrocarbon receptor repressor B asic helix-loop-helix (bHLH)-Per-aryl hydrocarbon receptor (AhR) nuclear translocator (ARNT)-SIM (PAS) proteins function as biological sensors that respond to physiological stimuli and environmental signals to mediate adaptive cellular responses. In general, these proteins form heterodimers that consist of a signal-induced subunit and an unregulated, ubiquitously expressed subunit (1). A member of the family of bHLH-PAS proteins is the AhR. Initially identified by Poland and Knutson (2) as a binding site for planar, nonhalogenated, and halogenated xenobiotics, in particular the highly toxic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the AhR was viewed for a long time as a mediator of xenobiotic-induced toxicity and carcinogenesis. However, mouse knockdown studies have revealed a role for the AhR beyond xenobiotic-induced toxicity and carcinogenesis. For example, the AhR has been shown to be involved in fetal liver development (3), immune cell modulation and differentiation (4-6), and gastrointestinal homeostasis (7, 8). The developmental defects observed in AhR Ϫ/Ϫ mice and the strong conservation of the AhR throughout evolution (for a review, see reference 9)

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“…Moreover, Per-ARNT-Sim (PAS) transcription factors belonging to different signalling circuits can compete for common binding partners such as ARNT (discussed below). Thus, misregulation of these proteins might contribute to tumour survival [9]. Noteworthily, the mutual regulation of PAS transcription factors on mRNA level was also mentioned in the literature, but appropriate citations are missing [22].…”

Section: Regulation Of Arnt By Other Factorsmentioning

confidence: 99%

“…They belong to the group of Per-ARNT-Sim (PAS) transcription factors which are characterised by the presence of a PAS domain (composed of PAS-A and PAS-B subdomains) required for protein-protein interactions. Therefore, all family members are able to form homo-and heterodimers among the group [9,25].…”

Section: Crosstalk Between Per-arnt-sim Transcription Factorsmentioning

confidence: 99%

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Hypoxic Upregulation of ARNT (HIF-1β): A Cell-Specific Attribute with Clinical Implications

Mandl¹,

Depping²

2017

Hypoxia and Human Diseases

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According to the current point of view described in the literature, the transcription factor aryl hydrocarbon receptor nuclear translocator (ARNT), also designated as hypoxiainducible factor (HIF)-1β, is constitutively expressed and not influenced by oxygen tension. However, a study published two decades ago provided early evidence regarding a hypoxia-dependent ARNT upregulation. This finding was subsequently challenged and neglected. Until now, only a limited number of publications focus on the regulation of ARNT in hypoxia. Therefore, appropriate studies and the putative mechanism mediating this cellular attribute are discussed. The advantages of an elevated ARNT expression level in tumour cells are delineated. This chapter provides an overview of hypoxia-inducible ARNT as an emerging concept in HIF biology.

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bHLH–PAS proteins in cancer

Cited by 220 publications

References 178 publications

Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation

Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation

A Molecular Mechanism To Switch the Aryl Hydrocarbon Receptor from a Transcription Factor to an E3 Ubiquitin Ligase

Hypoxic Upregulation of ARNT (HIF-1β): A Cell-Specific Attribute with Clinical Implications

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