Info

FIGURE 4. AhR-signaling pathway. Inactive AhR resides in the cytoplasm in complex with accessory proteins, including two HSP90 molecules, a cochaperon p-23, and an immunophilin-like protein, ARA9 (XAP2; AIP) (Carver et al., 1998; Kazlauskas et al., 2001). Binding of ligand to the AhR results in dissociation from the HSP90/p23/ARA9 complex and translocation of the ligand/ AhR/HSP90 complex into the nucleus. Once in the nucleus, AhR dissociates from the HSP90 molecules and dimerizes with Arnt (Reyes et al., 1992; Sogawa et al., 1995). The AhR/Arnt heterodimer binds to specific DNA sequences in the 5' regions of AhR-responsive genes termed xenobiotic response elements (XRE: 5'-GCGTG-3') (Matsushita et al., 1993; Watson and Hankinson, 1992). Data now indicate that the AhR/Arnt complex recruits coactivator proteins to the transcriptional start site, and alters nucleosomal configuration to facilitate transcriptional activation (Hankinson, 2005).

FIGURE 4. AhR-signaling pathway. Inactive AhR resides in the cytoplasm in complex with accessory proteins, including two HSP90 molecules, a cochaperon p-23, and an immunophilin-like protein, ARA9 (XAP2; AIP) (Carver et al., 1998; Kazlauskas et al., 2001). Binding of ligand to the AhR results in dissociation from the HSP90/p23/ARA9 complex and translocation of the ligand/ AhR/HSP90 complex into the nucleus. Once in the nucleus, AhR dissociates from the HSP90 molecules and dimerizes with Arnt (Reyes et al., 1992; Sogawa et al., 1995). The AhR/Arnt heterodimer binds to specific DNA sequences in the 5' regions of AhR-responsive genes termed xenobiotic response elements (XRE: 5'-GCGTG-3') (Matsushita et al., 1993; Watson and Hankinson, 1992). Data now indicate that the AhR/Arnt complex recruits coactivator proteins to the transcriptional start site, and alters nucleosomal configuration to facilitate transcriptional activation (Hankinson, 2005).

HSP90 molecules and dimerizes with another bHLH-PAS family member, Arnt (Reyes et al., 1992; Sogawa et al., 1995). The AhR/Arnt heterodimer is a transcription factor, binding to specific DNA sequences in the 5' regions of AhR-responsive genes termed xenobiotic response elements (XRE: 5'-GCGTG-3') (Matsushita et al., 1993; Watson and Hankinson, 1992) (Fig. 4). Data indicate that binding to the XRE does not require the TAD of AhR or Arnt; however, interaction with the CCAAT and TATA box for transcriptional activation requires the AhR TAD (Ko et al., 1997; Sogawa et al., 1995). Heterodimer binding to the XRE results in nucleosomal disruption and recruitment of transcription activation factors to the promoter region. This is mediated through direct binding to the transcriptional activation machinery: mouse AhR binds directly to TFIIB, whereas human AhR has been demonstrated to bind to both TBP and TFIIF (Rowlands et a/., 1996; Swanson and Yang, 1998; Watt et a/., 2005).

AhR binding to the XRE and transcriptional regulatory proteins is associated with interactions with a variety of coactivators that mediate nucleo-somal disruption. Coactivator CBP, a histone acetyltransferase (HAT), physically interacts with Arnt, as does SRC-1 and RIP140 (Beischlag et a/., 2002; Kobayashi et a/., 1997). The p160 HAT coactivators SRC-1, NCoA-1, and p/CIP associate with the cytochrome P450 1A1 (CYP1A1) promoter region following TCDD exposure (Hankinson, 2005). This, along with other data, indicates that the p160 coactivators are physiologically relevant coactivators for the AhR/Arnt-signaling pathway. Data also indicate a role for the Brahma/SWI-related gene protein (Brg-1) in AhR/Arnt-mediated changes in chromatin structure (Wang and Hankinson, 2002). A list of coactivator and corepressor proteins that interact with AhR/Arnt are shown in Table II.

Studies of the molecular mechanisms of the AhR/Arnt heterodimer have focused on the transcriptional activation of xenobiotic metabolizing genes, including Phase I drug-metabolizing enzymes, such as the cytochrome P450 (CYP450) family of monooxygenase enzymes (Fujii-Kuriyama et a/., 1992; Watson and Hankinson, 1992), as well as Phase II enzymes, including UGT1A1, GST-Ya subunit, and NADPH-quinone-oxido-reductase (reviewed in Mimura and Fujii-Kuriyama, 2003). A number of genes unrelated to xenobiotic metabolism are also activated by TCDD exposure. These include genes involved in growth control, such as TGF-a (Hankinson, 1995), TGF-;S2 (Hankinson, 1995), d-aminolevulinic acid synthetase (Hankinson, 1995), Bax (Matikainen et a/., 2001), and p27kip1 (Kolluri et a/., 1999); cytokines such as interleukin-1b (Sutter et a/., 1991; Yin et a/., 1994); other nuclear transcription factors such as c-Fos, Jun-B, c-Jun, and Jun-D (Hoffer et a/., 1996; Puga et a/., 1992); and plasminogen activator inhibitor-2 (PAI-2) and several matrix metalloproteinases, regulator of ECM proteolysis (Murphy et a/., 2004; Sutter et a/., 1991; Villano et a/., 2006; Yin et a/., 1994).

Although originally identified as the receptor for the PAH family of environmental contaminants, data indicate that the AhR binds to a variety of endogenous and exogenous compounds, including flavonoids, UV photo-products of tryptophan, as well as some synthetic retinoids (Carver and Bradfield, 1997; Denison et a/., 2002; Oberg et a/., 2005; Song et a/., 2002; Soprano and Soprano, 2003; Soprano et a/., 2001) (Fig. 5). The ability of synthetic retinoids to bind to and activate the AhR pathway has interesting implications for the cross talk between the AhR and RA pathways. Further, these retinoids were developed as therapies for skin disorders, inflammatory diseases, and for use as chemopreventatives (Nagpal and Chandraratna, 2000; Sporn and Suh, 2000; Thacher et a/., 2000); therefore, their ability to activate pathways other than the RA pathway is important to determining potential side effects. Experiments have shown that the pan-RAR antagonist

Synthetic ligands

JvJUU,

Was this article helpful?

0 0

Post a comment