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Suppression of the hypoxia inducible factor-1 function by redistributing the aryl hydrocarbon receptor nuclear translocator from nucleus to cytoplasm.

ABSTRACT: The aryl hydrocarbon receptor nuclear translocator (ARNT) heterodimerizes with hypoxia inducible factor-1? (HIF-1?), followed by upregulation of genes that are essential for carcinogenesis. We utilized a novel peptide (Ainp1) to address whether the HIF-1? signaling could be suppressed by an ARNT-mediated mechanism. Ainp1 suppresses the HIF-1?-dependent luciferase expression in Hep3B cells and this suppression can be reversed by ARNT. Ainp1 reduces the interaction between ARNT and HIF-1?, suppresses the formation of the HIF-1 gel shift complex, and suppresses the ARNT recruitment to the vegf promoter. These effects are partly mediated by redistribution of the nuclear ARNT contents to the cytoplasm.

SUBMITTER: Wang Y

PROVIDER: S-EPMC3319868 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Suppression of the hypoxia inducible factor-1 function by redistributing the aryl hydrocarbon receptor nuclear translocator from nucleus to cytoplasm.

Wang Yu Y Li Yanjie Y Wang Depeng D Li Yi Y Chang Abraham A Chan William K WK

Cancer letters 20120202 1

The aryl hydrocarbon receptor nuclear translocator (ARNT) heterodimerizes with hypoxia inducible factor-1α (HIF-1α), followed by upregulation of genes that are essential for carcinogenesis. We utilized a novel peptide (Ainp1) to address whether the HIF-1α signaling could be suppressed by an ARNT-mediated mechanism. Ainp1 suppresses the HIF-1α-dependent luciferase expression in Hep3B cells and this suppression can be reversed by ARNT. Ainp1 reduces the interaction between ARNT and HIF-1α, suppres ...[more]

PMID: 22306343

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Aryl hydrocarbon nuclear translocator (hypoxia inducible factor 1beta) activity is required more during early than late tumor growth.

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| S-EPMC2682336 | biostudies-literature

Aryl hydrocarbon receptor nuclear translocator in hepatocytes is required for aryl hydrocarbon receptor-mediated adaptive and toxic responses in liver.

Project description:The aryl hydrocarbon receptor (AHR) plays a central role in the toxic responses to halogenated dibenzo-p-dioxins ("dioxins"), in the metabolic adaptation to polycyclic aromatic hydrocarbons, and in the development of the mature vascular system. A number of lines of evidence support the idea that the regulation of adaptive metabolism requires an AHR partnership with the aryl hydrocarbon receptor nuclear translocator (ARNT). Yet, for AHR-dependent vascular development and dioxin toxicity, the role of ARNT is less certain. In fact, numerous models have been proposed over the years to suggest that the AHR signals in important ways via ARNT-independent events. In an effort to clarify the role of ARNT in AHR-mediated dioxin hepatotoxicity, we generated a conditional Arnt mouse model. Such a model was essential because global inactivation of Arnt results in embryonic lethality presumably due to this protein's role as a heterodimeric partner for the hypoxia-inducible factors (HIFs). Using a hepatocyte-specific Arnt deletion, we were able to demonstrate that hepatocyte ARNT is required for major aspects of AHR-mediated dioxin toxicity in the liver. Results from this conditional Arnt allele are also consistent with a model where hepatocyte ARNT is unrelated to AHR-mediated hepatovascular development. In sum, these data suggest that AHR-ARNT dimers within the hepatocyte direct the toxic and adaptive and developmental functions associated with the AHR and that developmental vascular events arise due to signaling in a distinct cell type expressing this dimeric pair.

| S-EPMC2984536 | biostudies-literature

Aryl Sulfonamides Induce Degradation of Aryl Hydrocarbon Receptor Nuclear Translocator through CRL4<sup>DCAF15</sup> E3 Ligase.

Project description:Aryl hydrocarbon receptor nuclear translocator (ARNT) plays an essential role in maintaining cellular homeostasis in response to environmental stress. Under conditions of hypoxia or xenobiotic exposure, ARNT regulates the subset of genes involved in adaptive responses, by forming heterodimers with hypoxia-inducible transcription factors (HIF1α and HIF2α) or aryl hydrocarbon receptor (AhR). Here, we have shown that ARNT interacts with DDB1 and CUL4-associated factor 15 (DCAF15), and the aryl sulfonamides, indisulam and E7820, induce its proteasomal degradation through Cullin-RING finger ligase 4 containing DCAF15 (CRL4DCAF15) E3 ligase. Moreover, the two known neo-substrates of aryl sulfonamide, RNA-binding motif protein 39 (RBM39) and RNA-binding motif protein 23 (RBM23), are not required for ARNT degradation. In line with this finding, aryl sulfonamides inhibited the transcriptional activities of HIFs and AhR associated with ARNT. Our results collectively support novel regulatory roles of aryl sulfonamides in both hypoxic and xenobiotic responses.

| S-EPMC7700843 | biostudies-literature

Potential Molecular Mechanism of Upregulated Aryl Hydrocarbon Receptor Nuclear Translocator 2 in Nasopharyngeal Carcinoma

Project description:Background Currently, the benefits of nasopharyngeal carcinoma (NPC) therapy are limited, and it is necessary to further explore possible therapeutic targets. Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) has been extensively studied in other cancer species, but little has been explored in NPC. The aim of this study was to verify the expression level of ARNT2 and its underlying mechanism in NPC. Methods Datasets containing ARNT2 mRNA expression levels were retrieved and collected from various databases to explore the expression status of ARNT2 in NPC. ARNT2-related coexpressed genes, differential expressed genes, and target genes were obtained for functional enrichment analysis. The potential target gene of ARNT2 and their regulatory relationship were studied through ChIP-seq data. CIBERSORTx was used to assess the immune infiltration of NPC, and the association with ARNT2 expression was calculated through correlation analysis. Results ARNT2 was upregulated and possessed an excellent discriminatory capability in NPC samples. ARNT2 positively correlated target genes were clustered in pathways in cancer, while negatively correlated target genes were enriched in immune-related pathway. The ChIP-seq information of ARNT2 and histone showed that prostaglandin-endoperoxide synthase 2 (PTGS2) was a potential target gene of ARNT2. CIBERSORTx revealed the immunity status in NPC, and ARNT2 expression was correlated with infiltration of five immune cells. Conclusions ARNT2 is overexpressed in NPC and may regulate PTGS2 to participate in the cancer process. ARNT2 serves as a key oncogenic target in NPC patients.

| S-EPMC9532129 | biostudies-literature

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