Pregnane X Receptor PXR Activates the GADD45β Gene, Eliciting the p38 MAPK Signal and Cell Migration

Kodama, Susumu; Negishi, Masahiko

doi:10.1074/jbc.m110.179812

Cited by 68 publications

(58 citation statements)

References 35 publications

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“…Our data are consistent with previous observations that PXR is antiapoptotic in colon (e.g., upregulates antiapoptotic BAG3, BIRC2, and MCL-1, while downregulating proapoptotic BAK1 and p53) (15,54) and ovarian cancer (20,55) and generally support the notion that PXR is associated with protection from xenobiotic damage (e.g., cellular drug resistance) (54,(56)(57)(58)(59). However our observations are in stark contrast to recent observations that PXR induces apoptosis in colon (60) and breast cancer (18) and predicts for significantly improved survival in esophageal cancer (61).…”

Section: Discussionsupporting

confidence: 81%

Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice

Wang¹,

Venkatesh²,

Li³

et al. 2011

J. Clin. Invest.

132

111

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The nuclear receptor pregnane X receptor (PXR) is activated by a range of xenochemicals, including chemotherapeutic drugs, and has been suggested to play a role in the development of tumor cell resistance to anticancer drugs. PXR also has been implicated as a regulator of the growth and apoptosis of colon tumors. Here, we have used a xenograft model of colon cancer to define a molecular mechanism that might underlie PXR-driven colon tumor growth and malignancy. Activation of PXR was found to be sufficient to enhance the neoplastic characteristics, including cell growth, invasion, and metastasis, of both human colon tumor cell lines and primary human colon cancer tissue xenografted into immunodeficient mice. Furthermore, we were able to show that this PXR-mediated phenotype required FGF19 signaling. PXR bound to the FGF19 promoter in both human colon tumor cells and "normal" intestinal crypt cells. However, while both cell types proliferated in response to PXR ligands, the FGF19 promoter was activated by PXR only in cancer cells. Taken together, these data indicate that colon cancer growth in the presence of a specific PXR ligand results from tumor-specific induction of FGF19. These observations may lead to improved therapeutic regimens for colon carcinomas.

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Section: Discussionsupporting

confidence: 81%

Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice

Wang¹,

Venkatesh²,

Li³

et al. 2011

J. Clin. Invest.

132

111

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“…Although recent papers have emphasized p38/ MAPK signaling and antiapoptotic functions, the widespread transcriptional changes in Gadd45b -/-mice led us to consider the role of Gadd45β as a coactivator, an effect demonstrated in an early paper by Yi et al (25). Our studies demonstrated relationships with CAR, and a recent paper by Kodama and Negishi showed that yet another nuclear receptor, PXR, stimulates Gadd45β expression and then interacts with the protein after it is expressed (51).…”

Section: Figurementioning

confidence: 84%

“…Its dramatic induction in the wild-type mouse more than doubles the total of all coactivators in the cell, altering the capacity for activating CAR target genes. Since Gadd45β definitely functions in pathways other than transcriptional coactivation (13,(16)(17)(18)(19)(20)(21)(22)(23)51), this unusually high expression might provide sufficient protein to impact transcription and also contribute to these other processes.…”

Section: Figurementioning

confidence: 99%

Gadd45β is an inducible coactivator of transcription that facilitates rapid liver growth in mice

Tian¹,

Huang²,

Hoffman³

et al. 2011

J. Clin. Invest.

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The growth arrest and DNA damage-inducible 45 (Gadd45) proteins act in many cellular processes. In the liver, Gadd45b (encoding Gadd45β) is the gene most strongly induced early during both compensatory regeneration and drug-induced hyperplasia. The latter response is associated with the dramatic and rapid hepatocyte growth that follows administration of the xenobiotic TCPOBOP (1,4-bis[2-(3,5)-dichoropyridyloxy] benzene), a ligand of the nuclear receptor constitutive androstane receptor (CAR). Here, we have shown that Gadd45b -/-mice have intact proliferative responses following administration of a single dose of TCPOBOP, but marked growth delays. Moreover, early transcriptional stimulation of CAR target genes was weaker in Gadd45b -/-mice than in wild-type animals, and more genes were downregulated. Gadd45β was then found to have a direct role in transcription by physically binding to CAR, and TCPOBOP treatment caused both proteins to localize to a regulatory element for the CAR target gene cytochrome P450 2b10 (Cyp2b10). Further analysis defined separate Gadd45β domains that mediated binding to CAR and transcriptional activation. Although baseline hepatic expression of Gadd45b was broadly comparable to that of other coactivators, its 140-fold stimulation by TCPO-BOP was striking and unique. The induction of Gadd45β is therefore a response that facilitates increased transcription, allowing rapid expansion of liver mass for protection against xenobiotic insults.

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“…3). Activation of the PXR has been reported to increase the expression of growth arrest and DNA damage-inducible 45b (GADD45b) (Kodama and Negishi, 2011), a protein that can block JNK1/2 activation by inhibiting its upstream kinase MKK7 (De Smaele et al, 2001;Papa et al, 2004;Larsen et al, 2006). Thus, we assessed whether PXR activation could modulate TNFa/IFNg-induced JNK1/2 activation in IEC monolayers.…”

Section: Resultsmentioning

confidence: 99%

Pregnane X Receptor Activation Attenuates Inflammation-Associated Intestinal Epithelial Barrier Dysfunction by Inhibiting Cytokine-Induced Myosin Light-Chain Kinase Expression and c-Jun N-Terminal Kinase 1/2 Activation

Garg¹,

Zhao²,

Erickson³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a complex etiology. IBD is thought to arise in genetically susceptible individuals in the context of aberrant interactions with the intestinal microbiota and other environmental risk factors. Recently, the pregnane X receptor (PXR) was identified as a sensor for microbial metabolites, whose activation can regulate the intestinal epithelial barrier. Mutations in NR1I2, the gene that encodes the PXR, have been linked to IBD, and in animal models, PXR deletion leads to barrier dysfunction. In the current study, we sought to assess the mechanism(s) through which the PXR regulates barrier function during inflammation. In Caco-2 intestinal epithelial cell monolayers, tumor necrosis factor-a/interferon-g exposure disrupted the barrier and triggered zonula occludens-1 relocalization, increased expression of myosin light-chain kinase (MLCK), and activation of c-Jun N-terminal kinase 1/2 (JNK1/2).Activation of the PXR [rifaximin and [[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenylidene]bis-phosphonic acid tetraethyl ester (SR12813); 10 mM] protected the barrier, an effect that was associated with attenuated MLCK expression and JNK1/2 activation. In vivo, activation of the PXR [pregnenolone 16a-carbonitrile (PCN)] attenuated barrier disruption induced by toll-like receptor 4 activation in wild-type, but not Pxr2/2, mice. Furthermore, PCN treatment protected the barrier in the dextran-sulfate sodium model of experimental colitis, an effect that was associated with reduced expression of mucosal MLCK and phosphorylated JNK1/2. Together, our data suggest that the PXR regulates the intestinal epithelial barrier during inflammation by modulating cytokineinduced MLCK expression and JNK1/2 activation. Thus, targeting the PXR may prove beneficial for the treatment of inflammationassociated barrier disruption in the context of IBD.

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Pregnane X Receptor PXR Activates the GADD45β Gene, Eliciting the p38 MAPK Signal and Cell Migration

Cited by 68 publications

References 35 publications

Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice

Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice

Gadd45β is an inducible coactivator of transcription that facilitates rapid liver growth in mice

Pregnane X Receptor Activation Attenuates Inflammation-Associated Intestinal Epithelial Barrier Dysfunction by Inhibiting Cytokine-Induced Myosin Light-Chain Kinase Expression and c-Jun N-Terminal Kinase 1/2 Activation

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