TCDD induces c-jun expression via a novel Ah (dioxin) receptor-mediated p38–MAPK-dependent pathway

Weiss, Carsten; Faust, Dagmar; Dürk, Heike; Kolluri, Siva Kumar; Pelzer, A.; Schneider, Sandra; Dietrich, Cornelia; Oesch, Franz; Göttlicher, Martin

doi:10.1038/sj.onc.1208679

Cited by 86 publications

(51 citation statements)

References 48 publications

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“…In addition, the TCDD-mediated inhibition in AP-1-binding activity was sustained up to 72 h post-LPS activation. Interestingly, TCDD treatment in nonactivated B cells produced a modest induction of AP-1 binding to several of the TRE within the Blimp-1 promoter, which is consistent with a prior report by Puga et al who showed TCDD-mediated induction of AP-1 binding in cultured mouse hepatoma cells and postulated a mechanism involving AhR-dependent p38-MAPK activation (Puga et al, 2000;Weiss et al, 2005). Presently, the molecular mechanism responsible for modulation of AP-1 activity in B cells by TCDD treatment is intriguing but difficult to explain in the context of AhR activation.…”

Section: S181supporting

confidence: 79%

The Long Winding Road toward Understanding the Molecular Mechanisms for B-Cell Suppression by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Sulentic

Kaminski

2010

Toxicological Sciences

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Suppression of humoral immune responses by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was first reported in the mid-1970s. Since this initial observation, much effort has been devoted by many laboratories toward elucidation of the cellular and molecular mechanisms responsible for the profound impairment of humoral immune responses by TCDD, which is characterized by decreased B cell to plasma cell differentiation and suppression of immunoglobulin production. These efforts have led to a significant body of research demonstrating a direct effect of TCDD on B-cell maturation and function as well as a requisite but as yet undefined role of the aryl hydrocarbon receptor (AhR) in these effects. Likewise, a number of molecular targets putatively involved in mediating B-cell dysfunction by TCDD, and other AhR ligands, have been identified. However, our current understanding has primarily relied on findings from mouse models, and the translation of this knowledge to effects on human B cells and humoral immunity in humans is less clear. Therefore, a current challenge is to determine how TCDD and the AhR affect human B cells. Efforts have been made in this direction but continued progress in developing adequate human models is needed. An in-depth discussion of these advances and limitations in elucidating the cellular and molecular mechanisms putatively involved in the suppression of B-cell function by TCDD as well as the implications on human diseases associated in epidemiological studies with exposure to TCDD and dioxin-like compounds is the primary focus of this review.Key Words: 2,3,7,8-tetrachlorodibenzo-p-dioxin; B cell; humoral immunity; immune suppression; AhR.Halogenated aromatic hydrocarbons such as the polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls are persistent environmental toxicants. The most potent of this class of chemicals is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is produced as a by-product during a variety of industrial and municipal processes, many of which involve the combustion of organic materials in the presence of chlorine. TCDD has generated much public concern due to several highly publicized incidents of human and wildlife exposure (reviewed by White and Birnbaum, 2009). Additionally, the sensitivity of rodent models to TCDD-induced toxicity has fueled concern regarding the potential health risks to humans. TCDD produces a broad range of biological effects in animal and cellular models including death, a generalized wasting syndrome, lymphoid involution (especially of the thymus), hepatotoxicity, cardiotoxicity, teratogenicity, developmental toxicity, carcinogenesis, neurotoxicity, immunotoxicity, and various biochemical effects (reviewed by Birnbaum and Tuomisto, 2000).Alterations in immune function, primarily immune suppression, have been observed in virtually every species studied and occurs at doses that do not produce obvious signs of toxicity in vivo and at noncytotoxic concentrations in vitro (Holsapple et al., 1991b;Kerkvliet, 2002). These alterations include ...

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Section: S181supporting

confidence: 79%

The Long Winding Road toward Understanding the Molecular Mechanisms for B-Cell Suppression by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Sulentic

Kaminski

2010

Toxicological Sciences

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“…Our observations showing activation of AhR and p38 MAPK signaling suggest the possibility that p38 MAPK signaling can be directly activated by AhR signaling, consistent with a recent study by Weiss et al (2005) showing AhR-dependent activation of p38 MAPK in response to the polyhalogenated aromatic hydrocarbon dioxin. In this context, it is noteworthy that exposure to dioxins predisposes to cholangiocarcinoma formation in rats and that the p38 MAPK signaling pathway is aberrantly activated and contributes to tumor growth in human cholangiocarcinoma (Tadlock and Patel, 2001;Walker et al, 2005).…”

supporting

confidence: 78%

Pifithrin-α Enhances Chemosensitivity by a p38 Mitogen-Activated Protein Kinase-Dependent Modulation of the Eukaryotic Initiation Factor 4E in Malignant Cholangiocytes

Wehbe

Henson

Lang

et al. 2006

J Pharmacol Exp Ther

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Pifithrin-␣ is the lead compound for a novel group of small molecules that are being developed for use as anticancer agents. The eukaryotic initiation factor 4E (eIF-4E) is overexpressed in many cancers, it can mediate sensitivity to therapy, and it may be regulated by p53. We examined the utility of pifithrin-␣ as an adjunct to therapy for the treatment of human cholangiocarcinoma, a tumor that is highly refractory to therapy, and we assessed the involvement of p53-dependent eIF-4E regulation in cellular responses to pifithrin-␣. The expression of eIF-4E was increased in human cholangiocarcinomas compared with normal liver. Modulation of eIF-4E expression by RNA interference enhanced the efficacy of gemcitabine in KMCH cholangiocarcinoma cells. Preincubation of KMCH cells with pifithrin-␣ enhanced gemcitabine-induced cytotoxicity in an eIF-4E-dependent manner. Furthermore, pifithrin-␣ increased eIF-4E phosphorylation at serine 209 via activation of p38 mitogen-activated protein kinase (MAPK). Pifithrin-␣ was shown to activate aryl hydrocarbon receptor (AhR) signaling and p38 MAPK activation. Sequencing analysis indicated the presence of a functionally inactivating p53 mutation in KMCH cells, and small interfering RNA to p53 did not modulate chemosensitization by pifithrin-␣. Pifithrin-␣ enhanced chemosensitivity by a mechanism independent of p53 and involving AhR and p38 MAPK deregulation of eIF-4E phosphorylation. Thus, pifithrin-␣ may prove useful for enhancing chemosensitivity in tumors with mutated p53. Moreover, modulation of eIF-4E is an attractive therapeutic target for intervention in cancer treatment.Pifithrin-␣ is a small molecule that was originally identified as a p53 inhibitor on chemical screens, and it represents a promising new class of therapeutic agents that are being developed and evaluated for use in cancer and neurodegenerative diseases (Komarov et al., 1999;Gudkov and Komarova, 2005). The utility of pifithrin-␣ in anticancer therapy remains undefined, partly due to a lack of knowledge regarding the mechanisms and targets by which it may exert cellular effects. Although originally identified as an inhibitor of p53, recent studies have shown that pifithrin-␣ can modulate intracellular signaling independent of p53 by acting as a potent agonist of the aryl hydrocarbon receptor (AhR) (Hoagland et al., 2005). Moreover, there is limited information about the potential interactions with other chemotherapeutic agents.We examined the utility of pifithrin-␣ as an adjunct to therapy for the treatment of human cholangiocarcinomas, malignancies arising from the biliary tract. These tumors are highly refractory to conventional treatments; consequently, they are associated with a poor prognosis. Recent reports indicate that global incidence and mortality of this aggressive cancer are increasing (Patel, 2006). Due to a limited ability to detect the tumor early, cholangiocarcinoma is often diagnosed at an advanced disease stage when curative resection is not possible. Thus, there is an urgent need f...

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“…TCDD has been reported to increase cytosolic Ca 2ϩ and also cause activation of PKC, PKA, and certain MAPKs (19,(42)(43)(44). In this regard, our data provide a mechanistic insight on how TCDD induces a change in Ca 2ϩ homeostasis through its direct action on mitochondrial function causing disruption of ⌬⌿m and culminating with the activation of mitochondria-to-nucleus stress signaling.…”

Section: Discussionmentioning

confidence: 82%

Dioxin-mediated tumor progression through activation of mitochondria-to-nucleus stress signaling

Biswas

Srinivasan

Anandatheerthavarada

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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TCDD induces c-jun expression via a novel Ah (dioxin) receptor-mediated p38–MAPK-dependent pathway

Cited by 86 publications

References 48 publications

The Long Winding Road toward Understanding the Molecular Mechanisms for B-Cell Suppression by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

The Long Winding Road toward Understanding the Molecular Mechanisms for B-Cell Suppression by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Pifithrin-α Enhances Chemosensitivity by a p38 Mitogen-Activated Protein Kinase-Dependent Modulation of the Eukaryotic Initiation Factor 4E in Malignant Cholangiocytes

Dioxin-mediated tumor progression through activation of mitochondria-to-nucleus stress signaling

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