The aryl hydrocarbon receptor constitutively represses c-myc transcription in human mammary tumor cells

Yang, Xiaoqing; Liu, Donghui; Murray, Tessa J.; Mitchell, Geoffrey C.; Hesterman, Eli V; Karchner, Sibel I.; Merson, Rebeka R.; Hahn, Mark E.; Sherr, David H.

doi:10.1038/sj.onc.1208938

Cited by 82 publications

(72 citation statements)

References 115 publications

(129 reference statements)

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“…However, in several ChIP experiments using untreated cells, we noticed variations in AhR/XRE binding intensity (data not shown), suggesting a periodic association of AhR with XRE-3 during regulation of constitutive AhRR transcription. A similar constitutive AhR/XRE-binding was reported for the c-myc gene (Yang et al, 2005). Upon treatment of the cells with 3-MC for the indicated times, we observed an oscillating binding-pattern of AhR, ARNT, and AhRR to the respective XRE-3 site of the AhRR intron I (Fig.…”

Section: Discussionsupporting

confidence: 54%

Analysis of the Transcriptional Regulation and Molecular Function of the Aryl Hydrocarbon Receptor Repressor in Human Cell Lines

Haarmann‐Stemmann¹,

Bothe²,

Kohli³

et al. 2007

Drug Metab Dispos

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Section: Discussionsupporting

confidence: 54%

Analysis of the Transcriptional Regulation and Molecular Function of the Aryl Hydrocarbon Receptor Repressor in Human Cell Lines

Haarmann‐Stemmann¹,

Bothe²,

Kohli³

et al. 2007

Drug Metab Dispos

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“…Furthermore, luciferase reporter assays have shown that this XRE motif is required for the effective transcriptional activation of the Vav3 gene by Ahr (35). Ligand-independent Ahr functions have been shown before in the regulation of TGF-␤ (18), Slug (19), and c-Myc (20). The mechanism that regulates this ligand-independent function of Ahr is unknown, although recent data indicate that this protein can be either up-or down-regulated by different biological and signaling stimuli, including high cell density (65), shear stress (66), calcium levels (19), protein-tyrosine kinases (67), or G-coupled receptors (68).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Factor Aryl Hydrocarbon Receptor (Ahr) Controls Cardiovascular and Respiratory Functions by Regulating the Expression of the Vav3 Proto-oncogene

Sauzeau

Carvajal-González

Riolobos

et al. 2011

Journal of Biological Chemistry

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“…12 Noteworthy, a nuclear-localized constitutively active AHR that blocks gene expression, probably by inducing local epigenetic modifications, has also been previously described. 43,44 Whether the AHR directly binds the p27 KIP1 promoter to repress transcription is not known up-to-now. Alternatively, the AHR may affect p27 KIP1 expression indirectly by modulating other transcription factors, such as HES-1 or c-myc, which are known to inhibit p27 KIP1 expression.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1

et al. 2013

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Exposure of keratinocytes (KC) to ultraviolet (UV) radiation results in the initiation of apoptosis, a protective mechanism that eliminates cells harboring irreparable DNA damage. Hence, a manipulation of UV-induced apoptosis may significantly influence photocarcinogenesis. We have discovered that the aryl hydrocarbon receptor (AHR), a key regulator of drug metabolism and an UVB-sensitive transcription factor, serves an anti-apoptotic function in UVB-irradiated human KC. Chemical and shRNA-mediated inhibition of AHR signaling sensitized KC to UVB-induced apoptosis by decreasing the expression of E2F1 and its target gene checkpoint kinase 1 (CHK1). The decreased expression of these cell-cycle regulators was due to an enhanced expression of p27 KIP1 and an associated decrease in phosphorylation of both cyclin-dependent kinase 2 and its substrate molecule retinoblastoma protein. The subsequent inhibition of E2F1 autoregulation and downstream CHK1 expression resulted in an enhanced susceptibility of damaged cells to undergo apoptosis. Accordingly, ectopic overexpression of either E2F1 or CHK1 in AHR-knockdown KC attenuated the observed sensitization to UVB-induced apoptosis. Using an AHR-knockout SKH-1 hairless mouse model, we next demonstrated the physiological relevance of the anti-apoptotic function of AHR. In contrast to their AHR-proficient littermates, the constitutive expression of E2F1 and CHK1 was significantly reduced in the skin of AHR-knockout mice. Accordingly, a single exposure of the animals to UVB resulted in an enhanced cleavage of caspase-3 in the skin of AHR-knockout mice. These results identify for the first time the AHR-E2F1-CHK1 axis as a novel anti-apoptotic pathway in KC, which may represent a suitable target for chemoprevention of non-melanoma skin cancer. With an annual incidence of two to three million new cases worldwide, non-melanoma skin cancer (NMSC) is one of the most frequent forms of cancer in humans (World Health Organization; http://www.who.int/uv/faq/skincancer/en/index1 .html). Typically, NMSCs, such as basal cell and squamous cell carcinomas, occur on sun-exposed areas of the skin, indicating that solar ultraviolet (UV) radiation, especially its UVB part (290-320 nm), is the most important etiological factor. 1,2 In fact, it is well established that UVB radiation gives rise to skin cancer without additional initiators or promoters and thus is a complete carcinogen. 1 Because of the thinning of the ozone layer, the increase in recreational sunbathing and the enhanced usage of UV tanning beds, the incidence of NMSC is expected to increase in future years, 1,2 underscoring the urgent need for novel preventives against UV-induced skin malignancies.When skin is exposed to solar radiation, high-energy UVB photons penetrate into the epidermis and initiate the so-called UVB response. 3 The main trigger of this stress response is the absorbance of UVB rays by DNA, which leads to the generation of highly mutagenic DNA photoproducts. 3,4 In addition, UVB exposure results in the formation...

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The aryl hydrocarbon receptor constitutively represses c-myc transcription in human mammary tumor cells

Cited by 82 publications

References 115 publications

Analysis of the Transcriptional Regulation and Molecular Function of the Aryl Hydrocarbon Receptor Repressor in Human Cell Lines

Analysis of the Transcriptional Regulation and Molecular Function of the Aryl Hydrocarbon Receptor Repressor in Human Cell Lines

Transcriptional Factor Aryl Hydrocarbon Receptor (Ahr) Controls Cardiovascular and Respiratory Functions by Regulating the Expression of the Vav3 Proto-oncogene

Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1

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