143

REVIEW

Thyroid hormone receptors regulate adipogenesis and carcinogenesis via crosstalk signaling with peroxisome proliferator-activated receptors

Changxue Lu and Sheue-Yann Cheng Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Room 5128, Bethesda, Maryland 20892-4264, USA

(Correspondence should be addressed to S-Y Cheng; Email: [email protected])

Abstract

Peroxisome proliferator-activated receptors (PPARs) and thyroid hormone receptors (TRs) are members of the nuclear receptor superfamily. They are ligand-dependent transcription factors that interact with their cognate hormone response elements in the promoters to regulate respective target gene expression to modulate cellular functions. While the transcription activity of each is regulated by their respective ligands, recent studies indicate that via multiple mechanisms PPARs and TRs crosstalk to affect diverse biological functions. Here, we review recent advances in the understanding of the molecular mechanisms and biological impact of crosstalk between these two important nuclear receptors, focusing on their roles in adipogenesis and carcinogenesis. Journal of Molecular Endocrinology (2010) 44, 143–154

Introduction (NR1C3; Fig. 1), are encoded by three different genes (PPARA, PPARD, and PPARG) located at chromosomes Peroxisome proliferator-activated receptors (PPARs) 22, 6, and 3 respectively. Upon ligand binding, PPARs and thyroid hormone receptors (TRs) are ligand- are recruited to peroxisome proliferator response dependent transcription receptors of the subfamily 1 elements (PPREs) in the regulatory region of target (NR1) in the nuclear receptor superfamily. The NR1 genes as heterodimers with the auxiliary factor RXR. group also includes retinoic acid receptors (RARs), With the PPAR/RXR heterodimers, either partner can Rev-erb, RAR-related orphan receptors (RORs), bind cognate ligands and elicit ligand-dependent oxysterol receptors (LXRs), vitamin D3 receptors transactivation (Kliewer et al. 1992). The canonical (VDRs), and the nuclear xenobiotic receptor (constitu- PPRE contains two direct repeats of the hormone tive androstane receptor, CAR). PPARs and TRs share a response element (HRE) half site (AGGTCA) with a conserved DNA-binding domain (DBD) and exert their 1 bp spacer in between (DR1; Kliewer et al. 1992, activity partly by heterodimerization with a common Tugwood et al. 1992). partner, the retinoid X receptor (RXR), to regulate the Natural and synthetic ligands have been reported for transcription of target genes. PPARs and TRs each have the three PPAR isotypes (Balakumar et al. 2007, diverse effects on developmental and metabolic pro- Bensinger & Tontonoz 2008; Table 1 and Fig. 2). For cesses as well as in diseases such as obesity, diabetes, and PPARa, ligands include natural unsaturated fatty acids cancer. The first part of this review describes current (FAs), leukotriene, hydroxyeicosatetraenoic acids understanding of PPAR and TR biology. The second (HETEs), and synthetic hypolipemia-inducing drugs part highlights recent advances in the understanding of such as fibrates. The PPARd ligands are less well known, molecular mechanisms underlying the PPAR–TR cross- but FAs have been suggested to be natural ligands for talks, with particular emphasis on the role of such this subtype of PPAR (Fyffe et al. 2006). Recent studies crosstalk in metabolism and carcinogenesis. identified a few more PPARd agonists, namely tetra- decylthioacetic acid (TTA), L-165041, and GW501516 Peroxisome proliferator-activated receptors (Berger et al. 1999, Oliver et al. 2001, Westergaard et al. 2001). For PPARg, endogenous ligands include PPARs, which consist of PPARa (NR1C1), PPARb/d polyunsaturated FAs, prostanoids, and oxidized FAs (NR1C2, hereafter referred to as PPARd), and PPARg found in low-density lipoproteins (Forman et al. 1995,

Journal of Molecular Endocrinology (2010) 44, 143–154 DOI: 10.1677/JME-09-0107 0952–5041/10/044–143 q 2010 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org

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DBD LBD glucose metabolism and insulin sensitization. That A Domains: A/B CD E/F PPARg also has a dominant role in adipogenesis is B PPAR isoforms: 1 100 174 468 α suggested by many loss-of-function studies both in vivo 1 73 146 441 and in vitro (Fajas et al. 2001). β/δ 86% 70% 1 109 183 477 γ1 83% 68% 1 29 137 211 505 Thyroid hormone receptors γ2 83% 68%

α In humans, TRs are encoded by two genes, THRA and C TR isoforms: 1 51 128 410 α1 THRB, located at chromosomes 17 and 3 respectively. 1 154 The THRA gene encodes three TRa (NR1A1) isoforms, ∆α1 1 51 128 370 409 492 TRa1, TRa2, and TRa3, which differ in their carboxyl α2 terminus as a result of alternative splicing of the 1 115 154 237 ∆α2 primary transcripts (Fig. 1). TRa1 binds triiodothy- 1 51 128 370 453 α3 ronine (T3) and activates or represses target genes, whereas TRa2andTRa3donotbindT3,and β D TR isoforms: 1 94 107 174 181 461 β1 may antagonize T3 action (Izumo & Mahdavi 1988, 1 147 160 227 234 514 Mitsuhashi et al. 1988, Macchia et al. 2001). The THRA β2 gene also yields two truncated proteins known as 1 23 36 103 110 390 β3 TRDa1 and TRDa2, which play a role in intestinal 1 8 288 ∆β3 development (Chassande et al. 1997, Plateroti et al. 2001). The THRB gene encodes two amino-terminal Figure 1 Schematic representation of the structures of PPARs TRb (NR1A2) protein variants – TRb1 and TRb2. In and TRs. (A) Modular domain structures of nuclear receptors in general. Two most conserved domains, DBD (C domain) and LBD rodents, the same gene also gives rise to TRb3 and a (E/F domain), are colored in gray and black respectively. (B) The truncated protein TRDb3, which lacks the DBD human PPAR homologs. Compared with the DBD of PPARa (Williams 2000, Harvey et al. 2007). (NR1C1), sequence homology is 86 and 83% in PPARb/d TRs bind to thyroid hormone response elements (NR1C2) and PPARg1/2 (NR1C3) respectively. In LBD, sequences are less conserved with only 70 and 68% of homology (TREs) in target genes as homodimers as well as for PPARb/d and PPARg1/2 respectively using the sequence of heterodimers with RXR. Most naturally occurring PPARa as a reference. (C and D) Structural comparison of rat positive TREs identified to date include two repeats of TRa isoforms (C) and rat TRb isoforms (D). The areas of identical the half site 50-AGGTCA-30, which is also shared by shading indicate conserved sequences among the isoforms. The PPREs arranged as a direct repeat with 4 bps between three major TRa isoforms (TRa1, a2, and a3) mainly differ in LBD at the carboxyl terminus; TRb isoforms (TRb1, b2, and b3) mainly the two half sites (DR4). Among known TREs, inverted differ in amino-terminal A/B domain. repeats (also called palindromes; e.g. GGTCAT- GACCTA) and everted repeats (e.g. GACCT(N6)- AGGTCA, N: any nucleotide) have also been reported Kliewer et al. 1995, Davies et al. 2001). Synthetic ligands (Glass et al. 1988, Brent et al. 1989, Farsetti et al. 1992, g for PPAR include anti-diabetic drugs, such as rosigli- Forman et al. 1992). TRs have also been shown to tazone and pioglitazone of the thiazolidinedione class. heterodimerize with other nuclear receptors, such as This wide variety of ligands for PPARs requires a flexible PPARs and VDRs (Bogazzi et al. 1994, Schrader et al. plasticity in the PPAR ligand-binding domain, which is 1994). In the presence of PPARa,TRb has binding suggested by the PPARg crystallized structure (Nolte affinity to a DR2 present in the myelin proteolipid et al. 1998). protein gene promoter but not to the classical TRE, PPARa is predominantly expressed in tissues with DR4, located in the malic enzyme gene. Upon thyroid high turnover rates of FA metabolism, such as liver, hormone stimulation, the DR2-driven reporter gene is brown adipose tissue (BAT), heart, and kidney. The activated by the TRb–PPARa heterodimer but not by target genes of PPARa are mainly involved in mito- TRa–PPARa,TRa–RXRb,orTRb–RXRb. Three amino chondrial and peroxisomal b-oxidation of FAs and acids in the D box of the DBD in TRb are critical for this apolipoprotein synthesis. PPARd is ubiquitously heterodimerization. The dissimilarity of the D boxes expressed in tissues. Its target genes are involved in between TRb and TRa may be responsible for this FA oxidation, fuel switch, mitochondrial respiration, isoform-dependent protein interaction and the DNA- and thermogenesis (Barish et al. 2006, Furnsinn et al. binding sequence specificity (Bogazzi et al.1994). 2007). PPARg expression is mainly found in BAT and In humans, the DBDs of TRs and PPARs are highly white adipose tissue (WAT) and, to a lesser extent, in homologous. Importantly, TRs and PPARs share the the large intestine, retina, and some immune cells (e.g. same proximal box (P-box) sequence in DBD, which is macrophage and T lymphocyte; Ricote et al. 1998, critical in sequence-specific recognition of HRE by Harris & Phipps 2001). Activation of PPARg affects NRs, while providing contact surface with the major

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Table 1 Ligands for peroxisome proliferator-activated receptors (PPARs) and thyroid hormone receptors (TRs)

Endogenous ligands Synthetic ligands

Receptors PPARa Polyunsaturated FAs, leukotriene B4 (LTB4), Clofibrate, fenofibrate, bezafibrate, gemfibrozil, HETE (Kliewer et al. 1997) ciprofibrate, Wy14 643 (Willson et al. 2000), BMS-687453, BMS-711939 (Mukherjee et al. 2008) PPARb/d Unsaturated or saturated long-chain Fas, prostacyclin, TTA, L-165,041, GW501516 eicosanoids, HODE (oxidized FA; Shureiqi et al. 2003) PPARg HODE (Schopfer et al. 2005), 15d-PGJ2 (Forman et al. Rosiglitazone, pioglitazone, rivoglitazone, troglitazone, 1995, Kliewer et al. 1995), azPC (Davies et al. 2001), giglitazone, farglitazar, GW7845 (Willson et al. 2000) LNO2 (unsaturated FA; Schopfer et al. 2005) TRa1T4,T3 CO23 (Ocasio & Scanlan 2006) TRb T4,T3 GC-1, KB-141, KB2115, MB07811 (Baxter & Webb 2009)

HETE, hydroxyeicosatetraenoic acid; HODE, hydroxyoctadecadienoic acid; azPC, hexadecyl azelaoyl phosphatidylcholine; LNO2, nitrolinoleic acid. groove of double-stranded DNA (Nelson et al. 1995, isoform (Lazar 1993). TRa1 is abundantly expressed in Rastinejad et al. 1995). the skeletal muscle, heart, and BAT, whereas TRa2 T3 is the most active form of thyroid hormone in mRNA is highly expressed in the brain. TRb1 is more target tissues, whereas L-thyroxine (T4) is the most expressed in the brain, liver, and kidney. TRb2 has a abundant thyroid hormone in the blood. Deiodination more restricted expression pattern, with major distri- 0 of T4 by either type I or type II 5 -deiodinase (DI or DII) bution in the anterior pituitary and hypothalamus in different tissues gives rise to the more active T3 (Hodin et al. 1989). The isoform-dependent distri- locally. Several synthetic agonists for TRs have also been bution further adds to the complexity in the regulation developed in the past decade (Table 1). Among them, of T3 actions. GC-1 and KB-141 have been extensively studied and show a higher affinity to the TRb subtype. In animal models, these TRb-specific agonists decrease plasma Crosstalk of PPARs and TRs in metabolism cholesterol and triglyceride levels, and induce fat loss and adipogenesis without apparent adverse effects on the heart and muscles (Grover et al. 2003, Baxter et al. 2004). Reciprocal regulation between TRs and PPARs Similar to PPARs, tissue-dependent distribution of TR isoforms regulates thyroid hormone actions in TRs play important roles, as do PPARs, in lipid target organs. Both TRa and TRb are expressed in mobilization, lipid degradation, FA oxidation, and virtually all tissues but the abundance varies for each glucose metabolism. By direct or indirect effect, thyroid

A TRα/β ligands B PPARα ligands C PPARβ/δ ligands D PPARγ ligands

Triiodothyronine (T3) LTB4 13(s)-HODE 15d-PGJ2 I I COOH OH OH COOH COOH HO O CH2CHCOOH NH OH O I 2 COOH Thyroxine (T4) 8(s)-HETE Prostacyclin LNO2 I I OH O NO2 CO H HO O CH CHCOOH 2 O 2 HO NH2 I I OH OH GC-1 Wy14,643 L-165,041 Troglitazone S O CH3 HO Me O CO2H H COOH N S O CO2H O N O H3C N Me O O H N HO CH3 O O HO Me Me CI CH3

CO23 Fenofibrate GW501516 Rosiglitazone H O O S HO I N O O CH3 O H C OH 3 CH3 N N N Me NH S O O O CH3 S O O H CI O F3C Me N O CH3

Figure 2 Ligand structures of TRs and PPARs. Chemical structures of several representative TR or PPAR ligands listed in Table 1 are shown. www.endocrinology-journals.org Journal of Molecular Endocrinology (2010) 44, 143–154

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status influences the expression of a number of genes activity of TRs in these processes (Festuccia et al. 2008). involved in lipid and glucose metabolism. For example, Regulation of DII by PPARg activation has also been TR isoform-specific regulation of hepatic genes involved identified in skeletal muscle in which the expression of in lipogenesis and FA oxidation has been implicated by DII was found to be induced by PPARg agonists, e.g. the cDNA array analysis of TRb knockout mice treated pioglitazone. Thus, via regulation of DII expression, with or without thyroid hormone (Flores-Morales et al. PPARg provides an additional level of regulation 2002). Among more than 200 hepatic genes responding via modulation of thyroid hormone metabolism w to T3 treatment, 60% of them are regulated by TRb (Grozovsky et al. 2009). and the remaining 40% are regulated through TRa. Studies of energy metabolism in rats show that the PPARa is one of the T3-regulated genes (Flores-Morales PPARd expression is modulated by T3–TR signaling. et al. 2002). By elevating the T3 level in hypothyroid rats, the In vivo studies reveal that TR and PPAR signaling can expression of mitochondrial PPARd in skeletal muscle similarly regulate some pathways in the lipid and is induced along with the increased mRNA level of glucose metabolism. In corticosteroid-induced diabetic mitochondria protein uncoupling protein 3 (de Lange mice, a decreased thyroid hormone level is accom- et al. 2007). More recently, in a study using transgenic panied by increased serum levels of insulin, total mice overexpressing the putative mitochondrial T3 cholesterol, triglycerides, and tissue lipid peroxidation. receptor p43 (an A/B domain truncated form of TRa1 Interestingly, the PPARg agonist rosiglitazone is able to (Casas et al. 1999, Wrutniak-Cabello et al. 2001)) in reverse the effect of dexamethasone and to increase T3 skeletal muscles, an increased protein level of PPARd and T4 levels in circulation (Jatwa et al. 2007). Moreover, was observed (Casas et al. 2008). Taken together, these in rats with a high-fat diet and in a hyperthyroid state, findings provide evidence that TR and PPAR can administration of the PPARa agonist Wy14,643 restores crosstalk by reciprocally affecting each other’s activity. glucose tolerance by enhancing glucose-stimulated insulin secretion and relieves the effect of hyperthy- roidism. These studies suggest that activation of PPARa Competition for the auxiliary factor RXR by PPAR and TR activity may restore the islet function affected by abnormal T3–TR signaling (Holness et al. 2008). It is reasonable to postulate that TRs and PPARs can Crosstalk between TR- and PPAR-signaling pathways regulate some common target genes involved in has also been implicated in the gene expression metabolic functions. As previously mentioned, tran- patterns in rats fed a high-fat diet. This diet induces scriptional activities of PPARs and TRs are determined an expression of the PPARa gene with a concomitant by several factors including hormone availability, decrease in expression in the liver of RARb,TRa1, and relative distribution of receptor isoforms, and the TRb1. In WAT, this diet increases the expression of abundance of the auxiliary factor, the RXR and other PPARg2 but reduces expression of RARa,TRa1, and coregulators. On the bases of the sequence homology TRb1(Redonnet et al. 2001). Similar results have been of HREs and the sharing of the heterodimerization obtained by using a specific PPARa inducer, bezafi- partner RXR, several mechanisms have been proposed brate, in rats. After a 10-day treatment with bezafibrate, to understand the cross-signaling between PPARs PPARa transcription is elevated with an activation of the and TRs. downstream gene, acyl-CoA oxidase (AOX), and a An early study examined the effect of PPARd on the decrease of maximal ligand-binding capacity of RARb binding of TRb to TREs and transcription activity and TRa1/b1(Bonilla et al. 2001). However, no RXRa (Meier-Heusler et al. 1995). Via eletrophoretic mobility mRNA expression is altered by the treatment (Bonilla shift assay (EMSA), PPARd was shown to reduce the et al. 2001, Redonnet et al. 2001). binding of TRb–RXRa to TRE, but PPARd itself had no PPARs have been shown to affect the thyroid affinity to the TRE either as a homodimer or hormone functions in thermogenesis in vivo. Adminis- heterodimer with RXRa. In a chloramphenicol acetyl- tration of the PPARg agonist rosiglitazone to male rats transferase (CAT) activity assay, however, PPARd shifts the energy usage to an anabolic state. Moreover, exerted an inhibitory effect on T3-induced transcription the activation of PPARg by rosiglitazone markedly activation by TRb on the TRE–CAT reporter gene even reduces plasma thyroid hormones, and mRNA levels in the presence of overexpressed RXRa protein in of DI and DII in the liver and BAT respectively. cells. These results suggest that PPARd inhibits the Rosiglitazone also decreases mRNA levels of the TRa1 transcriptional activity of TR action by competing for and TRb in BAT, and the TRa1 and TRa2 in retro- the heterodimerized partner RXR in the nucleus peritoneal WAT. These results explain the functions of (Meier-Heusler et al. 1995). PPARg in up-regulating thermogenesis-related genes in In another report, by site mutagenesis, a single WAT and BAT, while balancing the whole body leucine replacement by arginine at position 433 thermogenesis by down-regulating the transcription (L433R) of PPARa was shown to be critical in the

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Downloaded from Bioscientifica.com at 09/29/2021 11:23:24AM via free access Crosstalk of TR with PPAR signalling . CLUand S-Y CHENG 147 inhibition of TR action. This L443R alteration abolishes assay. However, thyroid hormone reverses the inhi- heterodimerization of PPARa with RXR and conse- bition of PPARa action by wild-type TRa but not by the quently its selective inhibitory effect on the TR action. P398H mutant. In vitro studies suggest that the P398H A mutational study also supports the idea that PPARa mutant itself is able to bind PPRE and reduce PPARa does not compete with TRs for binding of TREs. binding to PPREs. It is not clear whether P398H mutant Mutation in the P-box of hPPARa (C122S), which competes with PPARa for binding to RXR. The destroys the DNA-binding ability of PPARa, does not metabolic phenotype exhibited by P398H mutant affect its interference with TR transactivation. These mice is mediated in part via the unique properties of findings suggest that PPARa inhibits TRa transactiva- the P398H mutant receptor in interfering with PPARa tion by competing with TRa for binding to the auxiliary signaling (Liu et al. 2007). factor RXR (Juge-Aubry et al. 1995). In a similar manner as PPARs, TRs also inhibit the activity of several peroxisomal FA oxidation enzymes TR isoform-specific regulation of PPAR signaling regulated by both of these nuclear receptors. In in lipid metabolism transgenic mice expressing luciferase under the control The role of TR isoforms in lipid metabolism has been of promoter of the rat peroxisomal enoyl-CoA hydra- recently studied in vivo using a loss-of-function tase/3-hydroxyacyl-CoA dehydrogenase, T3 inhibits approach. Mice expressing an identical mutation ciprofibrate-induced luciferase activity in a TR-depen- (denoted as PV) in the corresponding C-terminal dent fashion. EMSA analyses reveal that regulation of region of TRa1(TRa1PV mouse; Kaneshige et al. the PPAR action by TR is through competition for the 2001)orTRb1 were created (TRbPV mouse; Kaneshige available RXR. Increasing the amount of RXR in cells et al. 2000). The PV mutation was identified in a patient partially reverses the TR inhibition on PPAR action, with resistance to thyroid hormone (RTH) who has a while heterodimerization-defective TR mutants lose the frameshift mutation in the C-terminal 14 amino acids of inhibitory activity. These results suggest that the TRb, resulting in a complete loss of T3-binding and peroxisome proliferators and T3-signaling pathways transcriptional capacity. This PV mutation exhibits converge through their common interaction with the potent dominant-negative activity. Compared with heterodimeric partner, RXR (Chu et al. 1995). TRa1PV mice, TRbPV mice exhibit no reduction in white adipose mass but have significant increases in Competition for HRE binding by PPARs and TRs serum-free FAs and total triglycerides (Ying et al. 2007). The impaired adipogenesis in the WAT is mediated by In addition to competition for binding to the common the repression of the expression of PPARg by TRa1PV, heterodimeric partner (i.e. RXR), TRs compete with leading to the reduced expression of genes involved PPARs for binding to HREs on certain target genes. in lipid synthesis (Ying et al. 2007). Thus, in the WAT, EMSA analysis shows that TRa binds to rat AOX PPRE, crosstalk with PPARg signaling is TR isoform- thus inhibiting the binding of PPAR to PPRE as dependent crosstalk. PPAR/RXRa heterodimers. However, as shown by The TR isoform-dependent crosstalk with PPARg is transient transfection assays, TRa stimulates transactiva- not limited to the WAT. Liver steatosis was observed in tion by PPAR/RXRa heterodimers on the AOX-PPRE TRbPV mice, while a reduced liver mass with scarcity of PV luciferase reporter gene in a T3-independent manner lipid drops was detected in TRa1 mice (Araki et al. with unknown mechanism (Hunter et al. 1996). More- 2009). In the liver of TRbPV mice, TRbPV activates over, comparison of reporter activity between wild-type PPARg signaling with increased expression of PPARg and DBD-mutated (C78S) TRa1 shows that TRa1 exerts and downstream lipogenic genes. With the increased a DBD-dependent, inhibitory effect on the PPAR- expression of the lipogenesis together with TRbPV- induced AOX gene transcription (Miyamoto et al. 1997). mediated decreased FA b-oxidation activity, excess An in vivo study using mouse models also implicates lipid accumulation is observed in the liver of TRbPV an interdependent relationship between TRs and mice. In contrast, TRa1PV functions to decrease the PPARs via competition for binding to HREs. Via expression of PPARg and its downstream lipogenic affecting the mRNA expression levels of many genes genes, leading to reduced fat mass in the liver of TRa1PV including carnitine palmitoyltransferase Ia (CPT-Ia), mice (Araki et al. 2009). These results indicate that AOX, acyl-CoA dehydrogenase, male mutant mice PPARg signaling in the liver is distinctively regulated by harboring a dominant-negative P398H-mutated TRa1 TR isoforms (Araki et al. 2009). Thus, these in vivo manifest visceral obesity, hyperleptinemia, reduced findings highlight the differential regulation by TR catecholamine-stimulated lipolysis in WAT, and hepatic isoforms of the PPARg signaling in lipid metabolism. steatosis (Liu et al. 2007). In the absence of T3, wild-type At present, the detailed molecular mechanisms by TRa1 and P398H mutant significantly reduce PPARa- which TR isoforms mediate differential crosstalk with mediated gene transcription in CPT-PPRE luciferase PPARg signaling in the liver and WAT are not known. www.endocrinology-journals.org Journal of Molecular Endocrinology (2010) 44, 143–154

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It is possible that similar to the earlier report by Human pancreatic carcinoma cells express Bogazzi et al. (1994),PPARg could have selectivity in functional PPARg that upon activation by its ligand, the heterodimerization with TRa or TRb, resulting in troglitazone, induces growth inhibition associated with differential functional consequences in lipid meta- G1 cell cycle arrest (Motomura et al. 2000). It has been bolism of these two target tissues. Alternatively, further shown that p27Kip1 can also play a key role in the different coregulatory proteins in these two target mediating the inhibitory effect by troglitazone (Moto- tissues could play differential modulatory roles, mura et al. 2000). A similar effect is also observed in leading to differential regulation in lipid metabolic human pancreatic cancer cell lines by using PPARg pathways. In view of the importance of the crosstalk ligands, 15-deoxy-D12,14-prostaglandin J2 (15d-PGJ2), of PPARg with TRs in the regulation of lipid and ciglitazaone. That approach showed 15d-PGJ2 metabolism, these issues would merit additional induces apoptosis through activation of caspases and studies in the future. reduces cell invasiveness by decreasing matrix metallo- proteinase (MMP)-2 and MMP-9 protein levels and activity (Hashimoto et al. 2002). These findings raise the Crosstalk signaling of PPARs and TRs in possibility that PPARg as a potential therapeutic target cancers for treatment of human pancreatic carcinomas. The role of PPARg in thyroid cancer was discovered PPARs in cancers by the identification of the fusion gene, the paired box 8 (PAX8)–PPARg,(PAX8–PPARg; Kroll et al. 2000). PPARs have been implicated in several cancers includ- Chromosomal t(2;3)(q13;p25) rearrangement results ing colon cancer, thyroid cancer, and pancreatic in the fusion of the thyroid transcription factor PAX8 carcinoma. However, their roles in the tumorigenesis gene to the PPARg gene and the expression of a of these cancers are controversial. Recent studies dominant-negative form of PPARg1 protein (PAX8– suggest that PPARd has a role in promoting colon PPARg fusion protein, PPFP). PAX8–PPARg rearrange- tumorigenesis. Mice with PPARd gene disruption in ment occurs in 25–70% of follicular thyroid cancers colonic epithelial cells have a decreased incidence of (FTC; Kroll et al. 2000). Immortalized human thyrocytes chemical carcinogen azoxymethane-induced colon or thyroid cancer cell lines expressing the PPFP have tumors (Zuo et al. 2009). Loss of PPARd also suppresses increased cell viability and growth (Gregory Powell et al. the elevated expression of vascular endothelial growth 2004, Espadinha et al. 2007). Array analysis shows that factor in tumor tissue (Zuo et al. 2009). By contrast, in K/K Min/C the expression of PPFP in cells leads to gene expression PPARd Apc (adenomatosis polyposis coli profiles with distinct transcriptional signature. PPFP gene, APC; multiple intestinal neoplasia, Min) mice, acts to upregulate genes associated with signal colon polyp formation is significantly greater than in C transduction, cell growth, and translational control. Min/ d Apc mice, suggesting that PPAR attenuates colon Concurrently, PPFP represses a large number of carcinogenesis and therefore can function as a tumor ribosomal protein and translational associated genes suppressor (Harman et al. 2004). (Lacroix et al. 2005, Lui et al. 2005, Giordano et al. PPARg has also been proposed as a tumor suppressor 2006). However, it is poorly understood how the fusion in colon carcinogenesis. In primary colorectal adeno- protein causes FTC. carcinomas, w8% of patients contain a loss-of-function More recently, a second PPARg gene rearrangement, mutation in one PPARg allele (Sarraf et al. 1999). g PPARg agonists can decrease premalignant intestinal CREB3L2–PPAR , was reported in a patient with FTC. g lesions in rats treated with azoxymethane (Tanaka et al. This fusion gene encodes a CREB3L2–PPAR fusion 2001). When PPARg is activated in primary colon protein that consists of the transactivation domain of tumors and colon cancer cell lines by PPARg agonists, CREB3L2 and functional domains of PPARg1. ! these cells appear to stop proliferation with reduced CREB3L2–PPARg occurs infrequently in FTC ( 3% growth and altered morphology of increased differen- of FTC). This fusion protein induces proliferation in C K tiation (Sarraf et al. 1998). Moreover, in Pparg / mice primary thyroid cells, but has lost the responsiveness to with azoxymethane treatment, a greater incidence of the PPARg agonists – troglitazone and rosiglitazone colon cancer with an increase of b-catenin level is (Lui et al. 2008). observed as compared with wild-type mice (Girnun et al. PPARd has also been implicated in thyroid carcino- 2002). However, an oncogenic role of PPARg in colon genesis. In vivo, a higher expression level of PPARd is cancer has also been suggested in several reports. For associated with increased proliferation in human example, activating of PPARg signaling by treating thyroid tumors. This increased PPARd can be induced ApcMin mice with the PPARg ligand troglitazone by thyroid mitogen (e.g. TSH and insulin) in normal increases significantly the number of colon polyps as primary thyrocytes that are cyclin E1 dependent compared with the untreated mice (Saez et al. 1998). (Zeng et al. 2008).

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TRs in cancers Interestingly, in a colon carcinoma cell line SW480 with genetic mutation in the APC gene, the high transcrip- T –TR signaling has also been implicated in the 3 tional activity of cyclin D1 promoter induced by tumorigenesis of the liver, breast, thyroid, and colon. b-catenin signaling is inhibited by overexpressing A variety of tumor cells respond to the stimulation TRb1 with the presence of T Natsume et al. 2003. of thyroid hormone to proliferate in vitro or in vivo 3 These studies provide evidence that T3–TR signaling (Short et al. 1980, Zhou-Li et al. 1992, Iishi et al. 1993, play key roles in carcinogenesis. Esquenet et al. 1995). For example, thyroid hormone enhances liver cancer cell invasion by inducing the expression of furin protein, a proprotein convertase Crosstalk signaling by PPARs and TRs in involved in tumor cell metastasis. The FURIN gene carcinogenesis contains putative TREs and Smad-binding sites. Under Studies described in the previous sections (see stimulation by thyroid hormone or the transforming section ‘Reciprocal regulation between TRs and growth factor b (TGFb), FURIN expression is induced, PPARs’) provide evidence that PPARs and TRs can and the increased protein level subsequently cleaves reciprocally inhibit transcriptional activity of the and activates MMPs such as MMP2 and MMP9 to genes involved in metabolic regulation either by increase tumor cell mobility (Chen et al. 2008). In competing for binding to the HREs or to RXR. These xenograft models, the number of metastatic foci in liver mechanisms can also be extended to describe the and lung is increased with overexpression of furin in molecular basis underlying the crosstalk signaling by HepG2 cells. In addition, an increased T3 level in the PPARs and TRs in the regulation of genes involved in hypothyroid severe combined immunodeficiency mice carcinogenesis. injected with HepG2-overexpressing TRa1 (HepG2– Compelling evidence to indicate that PPARg and TRa1) cells also leads to an increased number of TRb crosstalk affects thyroid carcinogenesis is revealed metastatic foci in liver and lung (Chen et al. 2008). in an animal model of FTC (TRbPV/PV mice; Suzuki et al. An anti-tumorigenic effect of thyroid hormone has 2002). As described in the section ‘TR isoform-specific also been reported for several tumor cell types regulation of PPAR signaling in lipid metabolism’, the (Ledda-Columbano et al. 1999, Martinez-Iglesias et al. TRbPV knockin mouse was initially created to model an 2009). T3 suppresses the growth and invasiveness of inheritable disease called RTH (Kaneshige et al. 2000); several human papillary thyroid cancer cell lines indeed, TRbPV mice faithfully recapitulate human RTH overexpressing wild-type TRb1 by inhibition of Akt- (Kaneshige et al. 2000). and MAPK-signaling pathways (Sedliarou et al. 2007). Remarkably, as homozygous TRbPV(TRbPV/PV) mice The suppression by TRb1 of growth and invasiveness age, they spontaneously develop FTC with a patho- has been similarly observed in hepatocarcinoma and logical progression similar to human FTC (Suzuki breast cancer cells. In responding to growth factors et al. 2002). Consistent with the findings in human including epidermal growth factor, insulin-like growth thyroid cancer (see section ‘PPARs in cancers’), a factor-1, and TGFb, the growth of hepatic and downregulation of the PPARg gene in thyroid tumors breast tumor cells is increased via activation of the of TRbPV/PV mice is made evident by decreased mRNA MAPK- and phosphatidylinositol 3-kinase (PI3K)- and protein levels. In vitro and in vivo findings indicate signaling pathways. However, an expression of TRb1 that the mutated TRbPV protein acts to inhibit the blocks the growth response of these tumor cells by ligand-dependent transcription of PPARg by competi- suppressing the MAPK- and PI3K-signaling pathways tive binding to PPREs (Ying et al. 2003, Araki et al. 2005). (Martinez-Iglesias et al. 2009). Cell-based transfection studies using PPRE-containing The clinical evidence from a case–control study reporters indicate that TRb1 acts to enhance the shows that hypothyroidism increases the risk of transcription activity of PPARg in the presence of hepatocellular carcinoma by two- to threefold (Hassan both T3 and troglitazone. TRbPV also binds to PPRE as et al. 2009). Furthermore, decreased expression of TRb1 does, but due to its lack of T3 binding, TRbPV acts TRb1 is also found in patients with colorectal adenoma to interfere with the enhancing effect of TRb1 on the and adenocarcinoma. Compared with normal colon transcription of PPARg (Ying et al. 2003). Treating epithelium, nuclear TRb1 is less frequently detected in TRbPV/PV mice with the PPARg agonist rosiglitazone colorectal cancer and its precursor abnormalities (such delays tumor progression and blocks metastatic spread as adenomas; Horkko et al. 2006). The reduced levels of (Kato et al. 2006). Moreover, when one allele of the TRb1 are also associated with the polypoid growth, PPARg gene is disrupted in TRbPV mice, progression of presence of K-ras mutations, and more advanced stages FTC is accelerated (Kato et al. 2006). These data suggest of colorectal cancers (Horkko et al. 2006). In APC gene- that the mutated TRbPV is a dominant-negative deficient mice, Wnt/b-catenin signaling is activated regulator of PPARg action. Two other PPARg agonists, with increased cyclin D1 expression (Hulit et al. 2004). ciglitazone and 15d-PGJ2, have also been shown to www.endocrinology-journals.org Journal of Molecular Endocrinology (2010) 44, 143–154

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decrease viability of a thyroid cancer cell line, CGRH gene regulation level (Fig. 3). Several lines of evidence W-2 (Chen et al. 2006). These two PPARg agonists support the notion that there is direct competition induce apoptosis of thyroid cancer cells through the between PPARs and TRs for HRE binding and/or caspase 3 and PTEN/Akt-signaling cascade, and they partnership with RXR. Moreover, the differential induce necrosis via the poly (ADP-ribose) polymerase binding of PPARs or TRs on DNA may also be (PARP) pathway (Chen et al. 2006). determined by the context of the promoter/enhancer of the target gene. The effect of PPARs and TRs may be cooperative or opposing during the crosstalk, but most Conclusions and future perspectives findings suggest the latter. Crosstalk between PPARs and TRs may also be mediated indirectly, such as a Recent studies have indicated that PPARs and TRs can reciprocal regulation of PPAR expression by TRs or vice crosstalk to affect diverse cellular functions. Evidence versa. The TR action may also be regulated indirectly by presented in this review reveals three possible molecu- PPARs, e.g. via its modulating the intermediate enzyme lar mechanisms that may account for the crosstalk at the genes, such as DII involved in T3 metabolism.

ABReciprocal regulation of Competition for HRE binding PPAR/TR expression RA PPAR ligands PPAR RXR

PPRE Target gene

PPAR TR

Direct/indirect

T3 PPAR

TR TR RXR PPRE Target gene

C Competition for RXR partnership (i) (ii) PPAR RXR TR RXR PPRE Target gene TRE Target gene

TR PPAR

TR RXR RXR PPAR

PPAR TR PPRE Target gene TRE Target gene

Figure 3 Proposed molecular mechanisms in PPAR–TR crosstalk. Three major mechanisms underlying the crosstalk of PPARs and TRs in target gene regulation are illustrated. (A) Reciprocal regulation of the PPAR and TR expression. The liganded PPAR or TR can reciprocally affect the gene expression of the other via direct and/or indirect regulation. (B) Competition for HRE binding. TRs competitively bind to PPRE of PPAR target genes. RA, retinoic acid. (C) Competition for RXR partnership. Either TRs (i) or PPARs (ii) compete with the other receptor for binding to RXR, resulting in decreased availability of RXR to reduce the transcriptional activity of PPAR target genes shown in (i) or the transcriptional activity of PPAR target genes shown in (ii).

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Recent exciting developments in the regulation of Bensinger SJ & Tontonoz P 2008 Integration of metabolism and lipid metabolism and carcinogenesis by PPARs and TRs inflammation by lipid-activated nuclear receptors. Nature 454 prompted us to focus in the present review on advances 470–477. Berger J, Leibowitz MD, Doebber TW, Elbrecht A, Zhang B, Zhou G, in understanding the crosstalk between PPARs and TRs. Biswas C, Cullinan CA, Hayes NS, Li Y et al. 1999 Novel peroxisome However, both PPARs and TRs have other important proliferator-activated receptor (PPAR) g and PPARdelta ligands cellular functions that may also converge as a result of produce distinct biological effects. Journal of Biological Chemistry 274 crosstalk between these two receptors. It is of great 6718–6725. interest to identify other biological processes and the Bergh JJ, Lin HY, Lansing L, Mohamed SN, Davis FB, Mousa S & Davis PJ 2005 Integrin alphaVbeta3 contains a cell surface target genes involved that are modulated by this mode receptor site for thyroid hormone that is linked to activation of of regulation. Furthermore, while the present review mitogen-activated protein kinase and induction of angiogenesis. focuses on the crosstalk of these two receptors via Endocrinology 146 2864–2871. nucleus-initiated genomic actions, the crosstalk may Bogazzi F, Hudson LD & Nikodem VM 1994 A novel heterodimeri- also be via nongenomic actions. The nongenomic zation partner for thyroid hormone receptor. Peroxisome proliferator-activated receptor. Journal of Biological Chemistry 269 actions of these two receptors have recently been 11683–11686. reported (Bergh et al. 2005, Gardner et al. 2005, Furuya Bonilla S, Redonnet A, Noel-Suberville C, Groubet R, Pallet V & et al. 2007). Thus, the crosstalk of PPARs and TRs could Higueret P 2001 Effect of a pharmacological activation of PPAR on also be mediated via the nongenomic actions. In view of the expression of RAR and TR in rat liver. Journal of Physiology and these considerations, a rapid development in the Biochemistry 57 1–8. understanding in the biological processes governed by Brent GA, Larsen PR, Harney JW, Koenig RJ & Moore DD 1989 Functional characterization of the rat growth hormone promoter the crosstalks of these two receptors would be elements required for induction by thyroid hormone with and forthcoming. without a co-transfected beta type thyroid hormone receptor. Journal of Biological Chemistry 264 178–182. Casas F, Rochard P, Rodier A, Cassar-Malek I, Marchal-Victorion S, Declaration of interest Wiesner RJ, Cabello G & Wrutniak C 1999 A variant form of the nuclear triiodothyronine receptor c-ErbAalpha1 plays a direct role The authors declare that there is no conflict of interest that could be in regulation of mitochondrial RNA synthesis. Molecular and Cellular perceived as prejudicing the impartiality of the research reported. Biology 19 7913–7924. Casas F, Pessemesse L, Grandemange S, Seyer P, Gueguen N, Baris O, Lepourry L, Cabello G & Wrutniak-Cabello C 2008 Overexpression Funding of the mitochondrial T3 receptor p43 induces a shift in skeletal muscle fiber types. PLoS ONE 3 e2501. Chassande O, Fraichard A, Gauthier K, Flamant F, Legrand C, Savatier P, The present research was supported by the Intramural Research Laudet V & Samarut J 1997 Identification of transcripts initiated Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. from an internal promoter in the c-erbA alpha locus that encode inhibitors of retinoic acid receptor-alpha and triiodothyronine receptor activities. Molecular Endocrinology 11 1278–1290. Chen Y, Wang SM, Wu JC & Huang SH 2006 Effects of PPARg agonists Acknowledgements on cell survival and focal adhesions in a Chinese thyroid carcinoma cell line. Journal of Cellular Biochemistry 98 1021–1035. We wish to thank all colleagues and collaborators who have Chen RN, Huang YH, Lin YC, Yeh CT, Liang Y, Chen SL & Lin KH 2008 contributed to the work described in this review. Thyroid hormone promotes cell invasion through activation of furin expression in human hepatoma cell lines. Endocrinology 149 3817–3831. References Chu R, Madison LD, Lin Y, Kopp P, Rao MS, Jameson JL & Reddy JK 1995 Thyroid hormone (T3) inhibits ciprofibrate-induced tran- scription of genes encoding beta-oxidation enzymes: cross Araki O, Ying H, Furuya F, Zhu X & Cheng SY 2005 Thyroid hormone talk between peroxisome proliferator and T signaling pathways. receptor beta mutants: dominant negative regulators of peroxisome 3 PNAS 92 11593–11597. proliferator-activated receptor g action. PNAS 102 16251–16256. Davies SS, Pontsler AV, Marathe GK, Harrison KA, Murphy RC, Araki O, Ying H, Zhu XG, Willingham MC & Cheng SY 2009 Distinct dysregulation of lipid metabolism by unliganded thyroid hormone Hinshaw JC, Prestwich GD, Hilaire AS, Prescott SM, Zimmerman GA receptor isoforms. Molecular Endocrinology 23 308–315. et al. 2001 Oxidized alkyl phospholipids are specific, high affinity Balakumar P, Rose M & Singh M 2007 PPAR ligands: are they potential peroxisome proliferator-activated receptor g ligands and agonists. agents for cardiovascular disorders? Pharmacology 80 1–10. Journal of Biological Chemistry 276 16015–16023. Barish GD, Narkar VA & Evans RM 2006 PPAR delta: a dagger in Espadinha C, Cavaco BM & Leite V 2007 PAX8PPARg stimulates cell the heart of the metabolic syndrome. Journal of Clinical Investigation viability and modulates expression of thyroid-specific genes in a 116 590–597. human thyroid cell line. Thyroid 17 497–509. Baxter JD & Webb P 2009 Thyroid hormone mimetics: potential Esquenet M, Swinnen JV, Heyns W & Verhoeven G 1995 Triiodothy- applications in atherosclerosis, obesity and type 2 diabetes. Nature ronine modulates growth, secretory function and androgen Reviews. Drug Discovery 8 308–320. receptor concentration in the prostatic carcinoma cell line LNCaP. Baxter JD, Webb P, Grover G & Scanlan TS 2004 Selective activation of Molecular and Cellular Endocrinology 109 105–111. thyroid hormone signaling pathways by GC-1: a new approach to Fajas L, Debril MB & Auwerx J 2001 Peroxisome proliferator-activated controlling cholesterol and body weight. Trends in Endocrinology receptor-g: from adipogenesis to carcinogenesis. Journal of Molecular and Metabolism 15 154–157. Endocrinology 27 1–9. www.endocrinology-journals.org Journal of Molecular Endocrinology (2010) 44, 143–154

Downloaded from Bioscientifica.com at 09/29/2021 11:23:24AM via free access 152 CLUand S-Y CHENG . Crosstalk of TR with PPAR signalling

Farsetti A, Desvergne B, Hallenbeck P, Robbins J & Nikodem VM 1992 Harris SG & Phipps RP 2001 The nuclear receptor PPAR g is expressed Characterization of myelin basic protein thyroid hormone response by mouse T lymphocytes and PPAR g agonists induce apoptosis. element and its function in the context of native and heterologous European Journal of Immunology 31 1098–1105. promoter. Journal of Biological Chemistry 267 15784–15788. Harvey CB, Bassett JH, Maruvada P, Yen PM & Williams GR 2007 The Festuccia WT, Oztezcan S, Laplante M, Berthiaume M, Michel C, rat thyroid hormone receptor (TR) Deltabeta3 displays cell-, TR Dohgu S, Denis RG, Brito MN, Brito NA, Miller DS et al. 2008 isoform-, and thyroid hormone response element-specific actions. Peroxisome proliferator-activated receptor-g-mediated positive Endocrinology 148 1764–1773. energy balance in the rat is associated with reduced sympathetic Hashimoto K, Ethridge RT & Evers BM 2002 Peroxisome proliferator- drive to adipose tissues and thyroid status. Endocrinology 149 activated receptor g ligand inhibits cell growth and invasion 2121–2130. of human pancreatic cancer cells. International Journal of Flores-Morales A, Gullberg H, Fernandez L, Stahlberg N, Lee NH, Gastrointestinal Cancer 32 7–22. Vennstrom B & Norstedt G 2002 Patterns of liver gene expression Hassan MM, Kaseb A, Li D, Patt YZ, Vauthey JN, Thomas MB, governed by TRbeta. Molecular Endocrinology 16 1257–1268. Curley SA, Spitz MR, Sherman SI, Abdalla EK et al. 2009 Forman BM, Casanova J, Raaka BM, Ghysdael J & Samuels HH 1992 Association between hypothyroidism and hepatocellular Half-site spacing and orientation determines whether thyroid carcinoma: a case–control study in the United States. Hepatology hormone and retinoic acid receptors and related factors bind to 49 1563–1570. DNA response elements as monomers, homodimers, or hetero- Hodin RA, Lazar MA, Wintman BI, Darling DS, Koenig RJ, Larsen PR, dimers. Molecular Endocrinology 6 429–442. Moore DD & Chin WW 1989 Identification of a thyroid hormone Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM & receptor that is pituitary-specific. Science 244 76–79. Evans RM 1995 15-Deoxy-D12,14-prostaglandin J2 is a ligand for Holness MJ, Greenwood GK, Smith ND & Sugden MC 2008 PPARalpha the adipocyte determination factor PPAR g. Cell 83 803–812. activation and increased dietary lipid oppose thyroid hormone Furnsinn C, Willson TM & Brunmair B 2007 Peroxisome proliferator- signaling and rescue impaired glucose-stimulated insulin secretion activated receptor-delta, a regulator of oxidative capacity, fuel in hyperthyroidism. American Journal of Physiology. Endocrinology and switching and cholesterol transport. Diabetologia 50 8–17. Metabolism 295 E1380–E1389. Furuya F, Guigon CJ, Zhao L, Lu C, Hanover JA & Cheng SY 2007 Horkko TT, Tuppurainen K, George SM, Jernvall P, Karttunen TJ & Nuclear receptor corepressor is a novel regulator of phosphatidyl- Makinen MJ 2006 Thyroid hormone receptor beta1 in normal inositol 3-kinase signaling. Molecular and Cellular Biology 27 colon and colorectal cancer-association with differentiation, 6116–6126. polypoid growth type and K-ras mutations. International Journal of Fyffe SA, Alphey MS, Buetow L, Smith TK, Ferguson MA, Sorensen MD, Cancer 118 1653–1659. Bjorkling F & Hunter WN 2006 Recombinant human PPAR- Hulit J, Wang C, Li Z, Albanese C, Rao M, Di Vizio D, Shah S, Byers SW, beta/delta ligand-binding domain is locked in an activated Mahmood R, Augenlicht LH et al. 2004 Cyclin D1 genetic conformation by endogenous fatty acids. Journal of Molecular Biology heterozygosity regulates colonic epithelial cell differentiation 356 1005–1013. and tumor number in ApcMin mice. Molecular and Cellular Biology Gardner OS, Dewar BJ & Graves LM 2005 Activation of mitogen- 24 7598–7611. activated protein kinases by peroxisome proliferator-activated Hunter J, Kassam A, Winrow CJ, Rachubinski RA & Capone JP 1996 receptor ligands: an example of nongenomic signaling. Molecular Crosstalk between the thyroid hormone and peroxisome Pharmacology 68 933–941. proliferator-activated receptors in regulating peroxisome Giordano TJ, Au AY, Kuick R, Thomas DG, Rhodes DR, Wilhelm KG Jr, proliferator-responsive genes. Molecular and Cellular Endocrinology Vinco M, Misek DE, Sanders D, Zhu Z et al. 2006 Delineation, 116 213–221. functional validation, and bioinformatic evaluation of gene Iishi H, Tatsuta M, Baba M, Yamamoto R & Taniguchi H 1993 expression in thyroid follicular carcinomas with the PAX8–PPARG Enhancement by thyroxine of gastric carcinogenesis induced by translocation. Clinical Cancer Research 12 1983–1993. N-methyl-N0-nitro-N-nitrosoguanidine in Wistar rats. British Girnun GD, Smith WM, Drori S, Sarraf P, Mueller E, Eng C, Nambiar P, Journal of Cancer 68 515–518. Rosenberg DW, Bronson RT, Edelmann W et al. 2002 Izumo S & Mahdavi V 1988 Thyroid hormone receptor alpha isoforms APC-dependent suppression of colon carcinogenesis by PPARg. generated by alternative splicing differentially activate myosin HC PNAS 99 13771–13776. gene transcription. Nature 334 539–542. Glass CK, Holloway JM, Devary OV & Rosenfeld MG 1988 The thyroid Jatwa R, Parmar HS, Panda S & Kar A 2007 Amelioration of hormone receptor binds with opposite transcriptional effects to a corticosteroid-induced type 2 diabetes mellitus by rosiglitazone is common sequence motif in thyroid hormone and estrogen possibly mediated through stimulation of thyroid function and response elements. Cell 54 313–323. inhibition of tissue lipid peroxidation in mice. Basic Clinical Gregory Powell J, Wang X, Allard BL, Sahin M, Wang XL, Hay ID, Pharmacology & Toxicology 101 177–180. Hiddinga HJ, Deshpande SS, Kroll TG, Grebe SK et al. 2004 The Juge-Aubry CE, Gorla-Bajszczak A, Pernin A, Lemberger T, Wahli W, PAX8/PPARg fusion oncoprotein transforms immortalized human Burger AG & Meier CA 1995 Peroxisome proliferator-activated thyrocytes through a mechanism probably involving wild-type receptor mediates cross-talk with thyroid hormone receptor by PPARg inhibition. Oncogene 23 3634–3641. competition for retinoid X receptor. Possible role of a leucine Grover GJ, Mellstrom K, Ye L, Malm J, Li YL, Bladh LG, Sleph PG, zipper-like heptad repeat. Journal of Biological Chemistry 270 Smith MA, George R, Vennstrom B et al. 2003 Selective thyroid 18117–18122. hormone receptor-beta activation: a strategy for reduction of Kaneshige M, Kaneshige K, Zhu X, Dace A, Garrett L, Carter TA, weight, cholesterol, and lipoprotein (a) with reduced cardio- Kazlauskaite R, Pankratz DG, Wynshaw-Boris A, Refetoff S et al. 2000 vascular liability. PNAS 100 10067–10072. Mice with a targeted mutation in the thyroid hormone beta Grozovsky R, Ribich S, Rosene ML, Mulcahey MA, Huang SA, Patti ME, receptor gene exhibit impaired growth and resistance to thyroid Bianco AC & Kim BW 2009 Type 2 deiodinase expression is induced hormone. PNAS 97 13209–13214. by peroxisomal proliferator-activated receptor-g agonists in skeletal Kaneshige M, Suzuki H, Kaneshige K, Cheng J, Wimbrow H, myocytes. Endocrinology 150 1976–1983. Barlow C, Willingham MC & Cheng S 2001 A targeted dominant Harman FS, Nicol CJ, Marin HE, Ward JM, Gonzalez FJ & Peters JM negative mutation of the thyroid hormone alpha 1 receptor 2004 Peroxisome proliferator-activated receptor-delta attenuates causes increased mortality, infertility, and dwarfism in mice. colon carcinogenesis. Nature Medicine 10 481–483. PNAS 98 15095–15100.

Journal of Molecular Endocrinology (2010) 44, 143–154 www.endocrinology-journals.org

Downloaded from Bioscientifica.com at 09/29/2021 11:23:24AM via free access Crosstalk of TR with PPAR signalling . CLUand S-Y CHENG 153

Kato Y, Ying H, Zhao L, Furuya F, Araki O, Willingham MC & Cheng SY of peroxisome proliferator signaling pathways by thyroid hormone 2006 PPARg insufficiency promotes follicular thyroid carcinogen- receptor. Competitive binding to the response element. Journal of esis via activation of the nuclear factor-kappaB signaling pathway. Biological Chemistry 272 7752–7758. Oncogene 25 2736–2747. Motomura W, Okumura T, Takahashi N, Obara T & Kohgo Y 2000 Kliewer SA, Umesono K, Noonan DJ, Heyman RA & Evans RM 1992 Activation of peroxisome proliferator-activated receptor g by Convergence of 9-cis retinoic acid and peroxisome proliferator troglitazone inhibits cell growth through the increase of p27KiP1 in signalling pathways through heterodimer formation of their human. Pancreatic carcinoma cells. Cancer Research 60 5558–5564. receptors. Nature 358 771–774. Mukherjee R, Locke KT, Miao B, Meyers D, Monshizadegan H, Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC & Zhang R, Search D, Grimm D, Flynn M, O’Malley KM et al. 2008 Lehmann JM 1995 A prostaglandin J2 metabolite binds peroxisome Novel peroxisome proliferator-activated receptor a agonists lower proliferator-activated receptor g and promotes adipocyte low-density lipoprotein and triglycerides, raise high-density differentiation. Cell 83 813–819. lipoprotein, and synergistically increase cholesterol excretion with Kliewer SA, Sundseth SS, Jones SA, Brown PJ, Wisely GB, Koble CS, a liver X receptor agonist. Journal of Pharmacology and Experimental Devchand P, Wahli W, Willson TM, Lenhard JM et al. 1997 Fatty Therapeutics 327 716–726. acids and eicosanoids regulate gene expression through direct Natsume H, Sasaki S, Kitagawa M, Kashiwabara Y, Matsushita A, interactions with peroxisome proliferator-activated receptors alpha Nakano K, Nishiyama K, Nagayama K, Misawa H, Masuda H et al. and gamma. PNAS 94 4318–4323. 2003 Beta-catenin/Tcf-1-mediated transactivation of cyclin D1 Kroll TG, Sarraf P, Pecciarini L, Chen CJ, Mueller E, Spiegelman BM & promoter is negatively regulated by thyroid hormone. Biochemical Fletcher JA 2000 PAX8–PPARg1 fusion oncogene in human thyroid and Biophysical Research Communications 309 408–413. carcinoma. Science 289 1357–1360. Nelson CC, Hendy SC & Romaniuk PJ 1995 Relationship between Lacroix L, Lazar V, Michiels S, Ripoche H, Dessen P, Talbot M, Caillou P-box amino acid sequence and DNA binding specificity of the B, Levillain JP, Schlumberger M & Bidart JM 2005 Follicular thyroid thyroid hormone receptor. The effects of sequences flanking half- tumors with the PAX8–PPARg1 rearrangement display charac- sites in thyroid hormone response elements. Journal of Biological teristic genetic alterations. American Journal of Pathology 167 223–231. Chemistry 270 16988–16994. de Lange P, Feola A, Ragni M, Senese R, Moreno M, Lombardi A, Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, Silvestri E, Amat R, Villarroya F, Goglia F et al. 2007 Differential Rosenfeld MG, Willson TM, Glass CK & Milburn MV 1998 Ligand 3,5,30-triiodothyronine-mediated regulation of uncoupling protein binding and co-activator assembly of the peroxisome proliferator- 3 transcription: role of fatty acids. Endocrinology 148 4064–4072. activated receptor-g. Nature 395 137–143. Lazar MA 1993 Thyroid hormone receptors: multiple forms, multiple Ocasio CA & Scanlan TS 2006 Design and characterization of a thyroid possibilities. Endocrine Reviews 14 184–193. hormone receptor alpha (TRalpha)-specific agonist. ACS Chemical Ledda-Columbano GM, Perra A, Piga R, Pibiri M, Loi R, Shinozuka H Biology 1 585–593. 0 & Columbano A 1999 Cell proliferation induced by 3,3 ,5-triiodo-L- Oliver WR Jr, Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, thyronine is associated with a reduction in the number of Lewis MC, Winegar DA, Sznaidman ML, Lambert MH et al. 2001 preneoplastic hepatic lesions. Carcinogenesis 20 2299–2304. A selective peroxisome proliferator-activated receptor delta agonist Liu YY, Heymann RS, Moatamed F, Schultz JJ, Sobel D & Brent GA promotes reverse cholesterol transport. PNAS 98 5306–5311. 2007 A mutant thyroid hormone receptor alpha antagonizes Plateroti M, Gauthier K, Domon-Dell C, Freund J-N, Samarut J & peroxisome proliferator-activated receptor alpha signaling in vivo Chassande O 2001 Functional interference between thyroid and impairs fatty acid oxidation. Endocrinology 148 1206–1217. hormone receptor a (TRa) and natural truncated TRDa isoforms Lui WO, Foukakis T, Liden J, Thoppe SR, Dwight T, Hoog A, Zedenius in the control of intestine development. Molecular and Cellular J, Wallin G, Reimers M & Larsson C 2005 Expression profiling Biology 21 4761–4772. reveals a distinct transcription signature in follicular thyroid Rastinejad F, Perlmann T, Evans RM & Sigler PB 1995 Structural carcinomas with a PAX8–PPAR(gamma) fusion oncogene. Oncogene determinants of nuclear receptor assembly on DNA direct repeats. 24 1467–1476. Nature 375 203–211. Lui WO, Zeng L, Rehrmann V, Deshpande S, Tretiakova M, Kaplan EL, Redonnet A, Groubet R, Noel-Suberville C, Bonilla S, Martinez A & Leibiger I, Leibiger B, Enberg U, Hoog A et al. 2008 CREB3L2– Higueret P 2001 Exposure to an obesity-inducing diet early affects PPARg fusion mutation identifies a thyroid signaling pathway the pattern of expression of peroxisome proliferator, retinoic acid, regulated by intramembrane proteolysis. Cancer Research 68 and triiodothyronine nuclear receptors in the rat. Metabolism 50 7156–7164. 1161–1167. Macchia PE, Takeuchi Y, Kawai T, Cua K, Gauthier K, Chassande O, Ricote M, Li AC, Willson TM, Kelly CJ & Glass CK 1998 The Seo H, Hayashi Y, Samarut J, Murata Y et al. 2001 Increased peroxisome proliferator-activated receptor-g is a negative regulator sensitivity to thyroid hormone in mice with complete deficiency of macrophage activation. Nature 391 79–82. of thyroid hormone receptor alpha. PNAS 98 349–354. Saez E, Tontonoz P, Nelson MC, Alvarez JG, Ming UT, Baird SM, Martinez-Iglesias O, Garcia-Silva S, Tenbaum SP, Regadera J, Larcher F, Thomazy VA & Evans RM 1998 Activators of the nuclear receptor Paramio JM, Vennstrom B & Aranda A 2009 Thyroid hormone PPARg enhance colon polyp formation. Nature Medicine 4 receptor beta1 acts as a potent suppressor of tumor invasiveness and 1058–1061. metastasis. Cancer Research 69 501–509. Sarraf P, Mueller E, Jones D, King FJ, DeAngelo DJ, Partridge JB, Meier-Heusler SC, Zhu X, Juge-Aubry C, Pernin A, Burger AG, Holden SA, Chen LB, Singer S, Fletcher C et al. 1998 Differentiation Cheng SY & Meier CA 1995 Modulation of thyroid hormone and reversal of malignant changes in colon cancer through PPARg. action by mutant thyroid hormone receptors, c-erbA alpha 2 and Nature Medicine 4 1046–1052. peroxisome proliferator-activated receptor: evidence for different Sarraf P, Mueller E, Smith WM, Wright HM, Kum JB, Aaltonen LA, mechanisms of inhibition. Molecular and Cellular Endocrinology 107 de la Chapelle A, Spiegelman BM & Eng C 1999 Loss-of-function 55–66. mutations in PPAR g associated with human colon cancer. Molecular Mitsuhashi T, Tennyson GE & Nikodem VM 1988 Alternative splicing Cell 3 799–804. generates messages encoding rat c-erbA proteins that do not bind Schopfer FJ, Lin Y, Baker PR, Cui T, Garcia-Barrio M, Zhang J, Chen K, thyroid hormone. PNAS 85 5804–5808. Chen YE & Freeman BA 2005 Nitrolinoleic acid: an endogenous Miyamoto T, Kaneko A, Kakizawa T, Yajima H, Kamijo K, Sekine R, peroxisome proliferator-activated receptor g ligand. PNAS 102 Hiramatsu K, Nishii Y, Hashimoto T & Hashizume K 1997 Inhibition 2340–2345. www.endocrinology-journals.org Journal of Molecular Endocrinology (2010) 44, 143–154

Downloaded from Bioscientifica.com at 09/29/2021 11:23:24AM via free access 154 CLUand S-Y CHENG . Crosstalk of TR with PPAR signalling

Schrader M, Muller KM, Nayeri S, Kahlen JP & Carlberg C 1994 Williams GR 2000 Cloning and characterization of two novel thyroid Vitamin D3-thyroid hormone receptor heterodimer polarity directs hormone receptor beta isoforms. Molecular and Cellular Biology 20 ligand sensitivity of transactivation. Nature 370 382–386. 8329–8342. Sedliarou I, Matsuse M, Saenko V, Rogounovitch T, Nakazawa Y, Willson TM, Brown PJ, Sternbach DD & Henke BR 2000 The PPARs: Mitsutake N, Namba H, Nagayama Y & Yamashita S 2007 Over- from orphan receptors to drug discovery. Journal of Medicinal expression of wild-type THRbeta1 suppresses the growth and Chemistry 43 527–550. invasiveness of human papillary thyroid cancer cells. Anticancer Wrutniak-Cabello C, Casas F & Cabello G 2001 Thyroid hormone Research 27 3999–4009. action in mitochondria. Journal of Molecular Endocrinology 26 67–77. Short J, Klein K, Kibert L & Ove P 1980 Involvement of the Ying H, Suzuki H, Zhao L, Willingham MC, Meltzer P & Cheng SY 2003 lodothyronines in liver and hepatoma cell proliferation in the rat. Mutant thyroid hormone receptor beta represses the expression Cancer Research 40 2417–2422. and transcriptional activity of peroxisome proliferator-activated Shureiqi I, Jiang W, Zuo X, Wu Y, Stimmel JB, Leesnitzer LM, Morris JS, receptor g during thyroid carcinogenesis. Cancer Research 63 Fan HZ, Fischer SM & Lippman SM 2003 The 15-lipoxygenase-1 5274–5280. product 13-S-hydroxyoctadecadienoic acid down-regulates PPAR- Ying H, Araki O, Furuya F, Kato Y & Cheng SY 2007 Impaired delta to induce apoptosis in colorectal cancer cells. PNAS 100 adipogenesis caused by a mutated thyroid hormone alpha1 9968–9973. receptor. Molecular and Cellular Biology 27 2359–2371. Suzuki H, Willingham MC & Cheng SY 2002 Mice with a mutation in Zeng L, Geng Y, Tretiakova M, Yu X, Sicinski P & Kroll TG 2008 the thyroid hormone receptor beta gene spontaneously develop Peroxisome proliferator-activated receptor-delta induces thyroid carcinoma: a mouse model of thyroid carcinogenesis. cell proliferation by a cyclin E1-dependent mechanism Thyroid 12 963–969. and is up-regulated in thyroid tumors. Cancer Research 68 Tanaka T, Kohno H, Yoshitani S, Takashima S, Okumura A, 6578–6586. Murakami A & Hosokawa M 2001 Ligands for peroxisome Zhou-Li F, Albaladejo V, Joly-Pharaboz MO, Nicolas B & Andre J 1992 proliferator-activated receptors alpha and gamma inhibit Antiestrogens prevent the stimulatory effects of L-triiodothyronine chemically induced colitis and formation of aberrant crypt foci on cell proliferation. Endocrinology 130 1145–1152. in rats. Cancer Research 61 2424–2428. Zuo X, Peng Z, Moussalli MJ, Morris JS, Broaddus RR, Fischer SM & Tugwood JD, Issemann I, Anderson RG, Bundell KR, McPheat WL & Green S 1992 The mouse peroxisome proliferator activated Shureiqi I 2009 Targeted genetic disruption of peroxisome receptor recognizes a response element in the 50 flanking sequence proliferator-activated receptor-delta and colonic tumorigenesis. of the rat acyl CoA oxidase gene. EMBO Journal 11 433–439. Journal of the National Cancer Institute 101 762–767. Westergaard M, Henningsen J, Svendsen ML, Johansen C, Jensen UB, Schroder HD, Kratchmarova I, Berge RK, Iversen L, Bolund L et al. 2001 Modulation of keratinocyte gene expression and differen- Received in final form 28 August 2009 tiation by PPAR-selective ligands and tetradecylthioacetic acid. Accepted 6 September 2009 Journal of Investigative Dermatology 116 702–712. Made available online as an Accepted Preprint 9 September 2009

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