AhR promotes phosphorylation of ARNT isoform 1 in human T cell malignancies as a switch for optimal AhR activity

Bourner, Luke; Muro, Israel; Cooper, Amy M.; Choudhury, Barun K.; Bailey, Aaron O.; Russell, William K.; Khanipov, Kamil; Golovko, George; Wright, Casey W.

doi:10.1073/pnas.2114336119

Cited by 10 publications

(11 citation statements)

References 85 publications

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“…AhRR and TiPARP function to provide negative feedback on AhR’s transcriptional activity, while SIN3A, typically regarded as a transcriptional repressor, was found to function as an essential co-activator for the transcription of CYP1A1 [ 67 ]. An additional mechanism fine-tuning the function of AhR was recently identified [ 68 ]. Bourner et al found that differential expression levels of ARNT isoforms altered the transcriptional activity of AhR, and ARNT isoform-dependent regulation of AhR was shown to be dependent on phosphorylation by the AhR target gene casein kinase 2 [ 68 ].…”

Section: Review Of Ahr Biology and Signalingmentioning

confidence: 99%

“…An additional mechanism fine-tuning the function of AhR was recently identified [ 68 ]. Bourner et al found that differential expression levels of ARNT isoforms altered the transcriptional activity of AhR, and ARNT isoform-dependent regulation of AhR was shown to be dependent on phosphorylation by the AhR target gene casein kinase 2 [ 68 ].…”

Section: Review Of Ahr Biology and Signalingmentioning

confidence: 99%

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Tumor-Suppressive Functions of the Aryl Hydrocarbon Receptor (AhR) and AhR as a Therapeutic Target in Cancer

Elson

Kolluri

2023

Biology

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The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in regulating a wide range of biological responses. A diverse array of xenobiotics and endogenous small molecules bind to the receptor and drive unique phenotypic responses. Due in part to its role in mediating toxic responses to environmental pollutants, AhR activation has not been traditionally viewed as a viable therapeutic approach. Nonetheless, the expression and activation of AhR can inhibit the proliferation, migration, and survival of cancer cells, and many clinically approved drugs transcriptionally activate AhR. Identification of novel select modulators of AhR-regulated transcription that promote tumor suppression is an active area of investigation. The development of AhR-targeted anticancer agents requires a thorough understanding of the molecular mechanisms driving tumor suppression. Here, we summarized the tumor-suppressive mechanisms regulated by AhR with an emphasis on the endogenous functions of the receptor in opposing carcinogenesis. In multiple different cancer models, the deletion of AhR promotes increased tumorigenesis, but a precise understanding of the molecular cues and the genetic targets of AhR involved in this process is lacking. The intent of this review was to synthesize the evidence supporting AhR-dependent tumor suppression and distill insights for development of AhR-targeted cancer therapeutics.

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Section: Review Of Ahr Biology and Signalingmentioning

confidence: 99%

Section: Review Of Ahr Biology and Signalingmentioning

confidence: 99%

Tumor-Suppressive Functions of the Aryl Hydrocarbon Receptor (AhR) and AhR as a Therapeutic Target in Cancer

Elson

Kolluri

2023

Biology

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“…However, compared to the AHR, less is known about the regulation of ARNT. ARNT is expressed in most cells as two isoforms that vary in the presence or absence of a 45 amino acid segment [ 6 ]. Casey Wright from the University of Texas at Galveston, USA, reported that in human T cells, the level of AHR transcriptional activity is dependent on which isoform of ARNT heterodimerized with the AHR.…”

Section: Sessions and Presentationsmentioning

confidence: 99%

“…He found, using transcriptomics and molecular analyses, that a low intracellular ARNT isoform 1:3 ratio enhances AHR responsiveness to ligand activation but abrogates NF-kB-inducing stimuli. Activation of primary CD4 + T cells promoted a physiological increase in the ARNT isoform ratio that favors NF-κB signaling, which is further enhanced by suppression of AHR [ 6 ]. Karin Loser from the University of Oldenburg, Oldenburg, Germany, presented work on experimental autoimmune encephalomyelitis (EAE), a mouse model mimicking aspects of human multiple sclerosis.…”

Section: Sessions and Presentationsmentioning

confidence: 99%

The Ah Receptor from Toxicity to Therapeutics: Report from the 5th AHR Meeting at Penn State University, USA, June 2022

Perdew

Esser

Snyder

et al. 2023

IJMS

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The aryl hydrocarbon receptor (AHR) is a sensor of low-molecular-weight molecule signals that originate from environmental exposures, the microbiome, and host metabolism. Building upon initial studies examining anthropogenic chemical exposures, the list of AHR ligands of microbial, diet, and host metabolism origin continues to grow and has provided important clues as to the function of this enigmatic receptor. The AHR has now been shown to be directly involved in numerous biochemical pathways that influence host homeostasis, chronic disease development, and responses to toxic insults. As this field of study has continued to grow, it has become apparent that the AHR is an important novel target for cancer, metabolic diseases, skin conditions, and autoimmune disease. This meeting attempted to cover the scope of basic and applied research being performed to address possible applications of our basic knowledge of this receptor on therapeutic outcomes.

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“…1D). Among them, ELF1, IRF3, ZNF410, and ARNT may promote the development of inflammation or senescence [42][43][44][45]. ATF7 not only plays a repressive role in innate immunity [18], but also responds to intrinsic and extrinsic stresses [17], and thus was chosen as the candidate gene (Fig.…”

Section: Centenarians Display Lower Inflammation With Possible Atf7 I...mentioning

confidence: 99%

Longevity-Associated Transcription Factor ATF7 Promotes Healthspan by Suppressing Cellular Senescence and Systematic Inflammation

Huang¹,

Ge²,

Li³

et al. 2022

Aging and disease

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Aging is characterized by persistent low-grade systematic inflammation, which is largely responsible for the occurrence of various age-associated diseases. We and others have previously reported that long-lived people (such as centenarians) can delay the onset of or even escape certain major age-related diseases. Here, by screening blood transcriptome and inflammatory profiles, we found that long-lived individuals had a relatively lower inflammation level (IL6, TNFα), accompanied by up-regulation of activating transcription factor 7 (ATF7). Interestingly, ATF7 expression was gradually reduced during cellular senescence. Loss of ATF7 induced cellular senescence, while overexpression delayed senescence progress and senescence-associated secretory phenotype (SASP) secretion. We showed that the anti-senescence effects of ATF7 were achieved by inhibiting nuclear factor kappa B (NF-κB) signaling and increasing histone H3K9 dimethylation (H3K9me2). In Caenorhabditis elegans, ATF7 overexpression significantly suppressed aging biomarkers and extended lifespan. Our findings suggest that ATF7 is a longevity-promoting factor that lowers cellular senescence and inflammation in long-lived individuals.

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AhR promotes phosphorylation of ARNT isoform 1 in human T cell malignancies as a switch for optimal AhR activity

Cited by 10 publications

References 85 publications

Tumor-Suppressive Functions of the Aryl Hydrocarbon Receptor (AhR) and AhR as a Therapeutic Target in Cancer

Tumor-Suppressive Functions of the Aryl Hydrocarbon Receptor (AhR) and AhR as a Therapeutic Target in Cancer

The Ah Receptor from Toxicity to Therapeutics: Report from the 5th AHR Meeting at Penn State University, USA, June 2022

Longevity-Associated Transcription Factor ATF7 Promotes Healthspan by Suppressing Cellular Senescence and Systematic Inflammation

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