Structural basis for PPARγ transactivation by endocrine-disrupting organotin compounds

Harada, Shusaku; Hiromori, Youhei; Nakamura, Shota; Kawahara, Kazuki; Fukakusa, Shunsuke; Maruno, Takahiro; Noda, Masanori; Uchiyama, Susumu; Fukui, Kiichi; Nishikawa, J; Nagase, Hisamitsu; Kobayashi, Yuji; Yoshida, Takuya; Ohkubo, Tadayasu; Nakanishi, Takashi

doi:10.1038/srep08520

Cited by 59 publications

(78 citation statements)

References 28 publications

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“…TBT-exposure during puberty led to weight gain, insulin resistance, increased leptin, and fatty liver in male mice 42 . Structural studies confirmed that TBT possesses nanomolar binding affinity for RXR, whereas, a related organotin, triphenyltin, bound both PPARγ and RXRα avidly 43-44 . Organotins still remain the only obesogens for which a molecular mechanism has been delineated.…”

Section: A Brief History Of Obesogensmentioning

confidence: 86%

Obesogens: an emerging threat to public health

Janesick¹,

Blumberg²

2016

American Journal of Obstetrics and Gynecology

189

141

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Endocrine disrupting chemicals (EDCs) are defined as exogenous chemicals, or mixture of chemicals, that can interfere with any aspect of hormone action. The field of endocrine disruption is historically rooted in wildlife biology and reproductive endocrinology where EDCs are demonstrated contributors to infertility, premature puberty, endometriosis, and other disorders. Recently, EDCs have been implicated in metabolic syndrome and obesity. Adipose tissue is a true endocrine organ and, therefore, an organ which is highly susceptible to disturbance by EDCs. A subset of EDCs, called “obesogens” promote adiposity by altering programming of fat cell development, increasing energy storage in fat tissue, and interfering with neuroendocrine control of appetite and satiety. Obesity adds more than $200 billion to U.S. healthcare costs and the number of obese individuals continues to increase. Hence, there is an urgent, unmet need to understand the mechanisms underlying how exposures to certain EDCs may predispose our population to be obese. In this review, we discuss the history of obesogen discovery from its origins in reproductive biology to its latest role in the transgenerational inheritance of obesity in mice. We discuss the development of adipose tissue in an embryo, maintenance of adipocyte number in adults, how EDC disruption programs stem cells to preferentially make more adipocytes, the mechanisms by which chemicals can permanently alter the germline epigenome, and whether there are barriers to EDCs in the gametes.

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Section: A Brief History Of Obesogensmentioning

confidence: 86%

Obesogens: an emerging threat to public health

Janesick¹,

Blumberg²

2016

American Journal of Obstetrics and Gynecology

189

141

View full text Add to dashboard Cite

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“…We previously demonstrated that specific binding of organotin compounds is achieved through non-covalent ionic interactions between the tin atom and the sulfur atom of C432 of hRXRα or C285 of hPPARγ. 22,23) However, the either C432 mutation of hRXRα or C285 mutation of hPPARγ did not result in significant effect of the ligand activity of TPAs and TPBi, for each receptor (Figs. 4, 6).…”

Section: Discussionmentioning

confidence: 92%

“…The resulting mutant constructs are designated pBK-CMV-GAL4-hRXRαC432A, and pM-PPARγC285A, respectively. 22,23) The LBDs of hRXRα (amino acids 201-462) were subcloned into pGEX-4T (GE Healthcare Life Sciences, Buckinghamshire, U.K.). 20) The DNA sequence encoding hPPARγ was cloned into pGEX-2T (GE Healthcare Life Sciences).…”

Section: Chemicalsmentioning

confidence: 99%

“…[20][21][22][23][24] Briefly, for the RXR transactivation assay, the ligand-binding domain (LBD, encoding amino acids 201-462) of human RXRα (hRXRα) was fused to the Cterminal end of the GAL4 DNA-binding domain (amino acids 1-147) in the pBK-CMV expression vector (Agilent Technologies, Santa Clara, CA, U.S.A.) to yield pBK-CMV-GAL4-hRXRα. 20,22) For the PPARγ transactivation assay, full-length cDNA of human PPARγ (hPPARγ) was fused to the Cterminal end of the GAL4 DNA-binding domain in the pM expression vector (Clontech/TaKaRa-Bio, Kusatsu, Japan) to yield pM-hPPARγ. 23,24) GAL4-hRXRα mutant constructs in which C432 and GAL4-hPPARγ mutant construct in which C285 was mutated to alanine were generated by site-directed mutagenesis of the pBK-CMV-GAL4-hRXRα plasmid and the pM-hPPARγ plasmid, respectively, by using a PrimeSTAR Mutagenesis Basal Kit (TaKaRa Bio).…”

Section: Chemicalsmentioning

confidence: 99%

“…19) We previously reported that some organotin compounds act as nanomolar agonists of both RXR and PPARγ. [20][21][22][23] Our previous studies demonstrated that the potency of the effects induced by organotin compounds is related to the number of alkyl and aryl groups on the tin atom and that the order of potency is tri->tetra->di->mono-substituted. In addition, the potency of organotins for these nuclear receptors' transactivation varies according to which functional groups are present.…”

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confidence: 99%

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Ligand Activity of Group 15 Compounds Possessing Triphenyl Substituent for the RXR and PPARγ Nuclear Receptors

Hiromori

Ido

Aoki

et al. 2016

Biological & Pharmaceutical Bulletin

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We investigated the ability of group 15 compounds with a triphenyl substituent to bind to and activate human retinoic X receptor (RXR) and peroxisome proliferator-activated receptor (PPAR) γ and their ability to activate the receptor. Triphenylphosphine oxide (TPPO) transcriptionally activated both RXR and PPARγ. Triphenylbismuth (TPBi) transcriptionally activated PPARγ but not RXR. However, TPBi significantly inhibited RXR transcriptional activity induced by 9-cis retinoic acid (9cRA) and PPARγ transcriptional activity induced by rosiglitazone (Rosi). Triphenylarsine (TPAs) also significantly inhibited the 9cRA- and Rosi-induced transcriptional activity of both receptors, whereas TPAs alone had no effect on the transcriptional activity of RXR and PPARγ. Consistent with these results, TPAs and TPBi blocked the binding of [H]9cRA to RXR and of [H]Rosi to PPARγ in a competitive manner. However, contrary to the results of the reporter gene assay, TPPO did not compete with [H]9cRA and [H]Rosi for binding to RXR and PPARγ, respectively. Our findings indicate that 1) TPPO is a transcriptional activator-but not a ligand-of RXR and PPARγ; 2) TPBi is an antagonist of RXR and a partial agonist of PPARγ; and 3) TPAs is a dual antagonist of RXR and PPARγ. These results suggest that TPPO, TPAs, and TPBi are potential endocrine disrupters of the PPARγ-RXR signaling pathway.

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Triorganotin complexes in cancer chemotherapy: Mechanistic insights and future perspectives

Anasamy

Chee

Wong

et al. 2020

Applied Organom Chemis

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Current anticancer drug discovery and development efforts are aimed at identifying new complexes that can potently and selectively target DNA and modulate the functions of target proteins. Tin complexes, categorized as monoorganotin (RSnL3), diorganotin (R2SnL2), triorganotin (R3SnL), or tetraorganotin (R4SnL), are one of the most studied complexes in the metal‐based anticancer drug discovery and development field. Among these, diorganotins and triorganotins are widely reported to possess promising anticancer properties, with triorganotins offering several potential advantages over diorganotins, such as a higher total surface area causing higher lipophilicity and hence higher cytotoxicity in cancer cells. However, information on triorganotins' direct therapeutic targets, an in‐depth understanding of their mechanism of action, and useful therapeutic strategies are still lacking. In this review, we discuss the results from in vitro and in vivo mechanistic studies of triorganotin complexes as reported in recent years (2007–2019) and elaborate on the underlying mechanisms that could aid in the identification of triorganotin complex molecular targets. We conclude by identifying present obstacles faced by triorganotin complexes that avert their translation to the clinical phase and current strategies employed to overcome the aforementioned obstacles, and we offer considerations for their future development. These findings are anticipated to stimulate further developments of novel and innovative triorganotin complexes as anticancer drug candidates.

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Structural basis for PPARγ transactivation by endocrine-disrupting organotin compounds

Cited by 59 publications

References 28 publications

Obesogens: an emerging threat to public health

Obesogens: an emerging threat to public health

Ligand Activity of Group 15 Compounds Possessing Triphenyl Substituent for the RXR and PPARγ Nuclear Receptors

Triorganotin complexes in cancer chemotherapy: Mechanistic insights and future perspectives

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