Ah Receptor–Mediated Suppression of Liver Regeneration through NC-XRE–Driven p21<sup>Cip1</sup>Expression

Jackson, D. Paul; Li, Hui; Mitchell, Kristen; Joshi, Atul; Elferink, Cornelis

doi:10.1124/mol.113.089730

Cited by 61 publications

(71 citation statements)

References 43 publications

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“…Furthermore, p21 KO mice have been reported to exhibit enhanced liver regeneration in both partial and extreme hepatectomies (33–35). Consequently, it is possible that direct blockade of p21 could be considered as an alternative approach to induce a regenerative liver response, but further research into this pathway would be required.…”

Section: The Role Of the Cell Cycle In Regenerationmentioning

confidence: 99%

Oxygen, Metabolism, and Regeneration: Lessons from Mice

Heber‐Katz

2017

Trends in Molecular Medicine

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The discovery that the Murphy Roths Large (MRL) mouse strain is a fully competent, epimorphic tissue regenerator, proved that the machinery of regeneration was preserved through evolution from hydra, to salamanders, to mammals. Such concepts have allowed translation of the biology of amphibians -- and their ability to regenerate -- to a mammalian context. In particular, the ancient hypoxia inducible factor (HIF-1α) pathway, operating through prolyl hydroxylase domain proteins (PHDs), was identified as a central player in mouse regeneration. Thus, the possibility of targeting PHDs or other HIF-1α modifiers to effectively recreate the amphibian regenerative state has emerged. We posit that these regenerative pathways are critical in mammals. Moreover, the current approved use of PHD inhibitors in the clinic should allow fast-track translation from mouse studies to drug-based regenerative therapy in humans.

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Section: The Role Of the Cell Cycle In Regenerationmentioning

confidence: 99%

Oxygen, Metabolism, and Regeneration: Lessons from Mice

Heber‐Katz

2017

Trends in Molecular Medicine

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“…In addition to the classical nuclear AhR:Arnt-mediated response, non-genomic AhR pathways have also been reported, 31 and recent studies show that a nuclear AhR-Krüppel-like factor 4 (KLF4) complex mediates activation of p21 and plasminogen activator inhibitor-1 through a non-consensus-XRE. 32, 33 …”

Section: Introductionmentioning

confidence: 99%

Omeprazole Inhibits Pancreatic Cancer Cell Invasion through a Nongenomic Aryl Hydrocarbon Receptor Pathway

Jin

Kim

Safe

2015

Chem. Res. Toxicol.

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Omeprazole and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are aryl hydrocarbon receptor (AhR) agonist that inhibit invasion of breast cancer cell through inhibition of CXCR4 transcription. Treatment of highly invasive Panc1 pancreatic cancer cells with TCDD, omeprazole and seven other AhR-active pharmaceuticals showed that only omeprazole and tranilast but not TCDD inhibited invasion in a Boyden chamber assay. Similar results were observed in MiaPaCa2 cells, another quasimensenchymal pancreatic ductal adenocarcinoma (QM-PDA) pancreatic cancer cell line, whereas invasion was not observed in BxPC3 or L3.6pL cells which are classified as “classical” (less invasive) pancreatic cancer cells. It was also observed that in the QM-PDA cells that TCDD, omeprazole and tranilast did not induce CYP1A1 or CXCR4 and treatment with these compounds did not result in nuclear uptake of the AhR. In contrast, treatment of BxPC3 and L3.6pL cells with these AhR ligands resulted in induction of CYP1A1 (by TCDD) and nuclear uptake of the AhR which was similar to that observed for Ah-responsive MDA-MB-468 breast and HepG2 liver cancer cell lines. Results of AhR and AhR nuclear translocator (Arnt) knockdown experiments in Panc1 and MiaPaCa2 cells demonstrate that omeprazole- and tranilast-mediated inhibition of invasion was AhR-dependent but Arnt-independent. These results demonstrate that in the most highly invasive sub-type of pancreatic cancer cells (QM-PDA), the selective AhR modulators omeprazole and tranilast inhibit invasion through a non-genomic AhR pathway.

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“…Ligand-dependent activation of the AhR results in formation of a nuclear complex with the AhR nuclear translocator (Arnt) protein which binds cis-xenobiotic response elements (XREs) in the Cyp1a1 and other target gene promoters (Poland et al, 1976;Hankinson, 1995;Whitlock, 1999). However, several nonclassic pathways have been discovered, and these include AhR interactions with other nuclear partners, binding to nonconsensus cis-promoter elements, and also responses that are associated with the extranuclear AhR (Blankenship and Matsumura, 1997;Kim et al, 2000;Singh et al, 2007;Vogel et al, 2007;Li and Matsumura, 2008;Dong and Matsumura, 2009;Denison et al, 2011;Jackson et al, 2014;Vogel et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Activity of Tryptophan Metabolites in Young Adult Mouse Colonocytes

et al. 2015

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The tryptophan microbiota metabolites indole-3-acetate, indole-3-aldehyde, indole, and tryptamine are aryl hydrocarbon receptor (AhR) ligands, and in this study we investigated their AhR agonist and antagonist activities in nontransformed young adult mouse colonocyte (YAMC) cells. Using Cyp1a1 mRNA as an Ah-responsive end point, we observed that the tryptophan metabolites were weak AhR agonists and partial antagonists in YAMC cells, and the pattern of activity was different from that previously observed in CaCo2 colon cancer cells. However, expansion of the end points to other Ah-responsive genes including the Cyp1b1, the AhR repressor (Ahrr), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP-ribose) polymerase (TiParp) revealed a highly complex pattern of AhR agonist/antagonist activities that were both ligand-and genedependent. For example, the magnitude of induction of Cyp1b1 mRNA was similar for TCDD, tryptamine, and indole-3-acetate, whereas lower induction was observed for indole and indole-3-aldehyde was inactive. These results suggest that the tryptophan metabolites identified in microbiota are selective AhR modulators.

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Ah Receptor–Mediated Suppression of Liver Regeneration through NC-XRE–Driven p21^Cip1Expression

Abstract: Previous studies in hepatocyte-derived cell lines and the whole liver established that the aryl hydrocarbon receptor (AhR) can disrupt G 1

Cited by 61 publications

References 43 publications

Oxygen, Metabolism, and Regeneration: Lessons from Mice

Oxygen, Metabolism, and Regeneration: Lessons from Mice

Omeprazole Inhibits Pancreatic Cancer Cell Invasion through a Nongenomic Aryl Hydrocarbon Receptor Pathway

Aryl Hydrocarbon Receptor Activity of Tryptophan Metabolites in Young Adult Mouse Colonocytes

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Ah Receptor–Mediated Suppression of Liver Regeneration through NC-XRE–Driven p21Cip1Expression

Abstract: Previous studies in hepatocyte-derived cell lines and the whole liver established that the aryl hydrocarbon receptor (AhR) can disrupt G 1

Cited by 61 publications

References 43 publications

Oxygen, Metabolism, and Regeneration: Lessons from Mice

Oxygen, Metabolism, and Regeneration: Lessons from Mice

Omeprazole Inhibits Pancreatic Cancer Cell Invasion through a Nongenomic Aryl Hydrocarbon Receptor Pathway

Aryl Hydrocarbon Receptor Activity of Tryptophan Metabolites in Young Adult Mouse Colonocytes

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Ah Receptor–Mediated Suppression of Liver Regeneration through NC-XRE–Driven p21^Cip1Expression