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ABSTRACT: PHF2 is a JmjC family histone demethylase that removes the methyl group from H3K9me2 and works as a coactivator for several metabolism-related transcription factors. In this study, we examined the in vivo role of PHF2 in mice. We generated Phf2 floxed mice, systemic Phf2 null mice by crossing Phf2 floxed mice with CMV-Cre transgenic mice, and tamoxifen-inducible Phf2 knockout mice by crossing Phf2 floxed mice with Cre-ERT2 transgenic mice. Systemic Phf2 null mice had partial neonatal death and growth retardation and exhibited less adipose tissue and reduced adipocyte numbers compared with control littermates. Tamoxifen-induced conditional knockout of PHF2 resulted in impaired adipogenesis in stromal vascular cells from the adipose tissue of tamoxifen-inducible Phf2 knockout mice as well as of Phf2 knocked-down 3T3-L1 cells. PHF2 interacts with CEBPA and demethylates H3K9me2 in the promoters of CEBPA-regulated adipogenic genes. These findings suggest that PHF2 histone demethylase potentiates adipogenesis through interaction with CEBPA in vivo. Taken together, PHF2 may be a novel therapeutic target in the treatment of obesity and the metabolic syndrome.
Diabetes 12/2012; · 8.29 Impact Factor
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Ichiro Takada,
Masatomo Mihara,
Miyuki Suzawa, Fumiaki Ohtake,
Shinji Kobayashi,
Mamoru Igarashi,
Min-Young Youn,
Ken-Ichi Takeyama,
Takashi Nakamura,
Yoshihiro Mezaki,
Shinichiro Takezawa,
Yoshiko Yogiashi,
Hirochika Kitagawa,
Gen Yamada,
Shinji Takada,
Yasuhiro Minami,
Hiroshi Shibuya,
Kunihiro Matsumoto,
Shigeaki Kato
Nature Cell Biology 12/2012; 14(12):1345. · 19.49 Impact Factor
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Mi-Sun Kim,
Takeshi Kondo,
Ichiro Takada,
Min-Young Youn,
Yoko Yamamoto,
Sayuri Takahashi,
Takahiro Matsumoto,
Sally Fujiyama,
Yuko Shirode,
Ikuko Yamaoka,
Hirochika Kitagawa,
Ken-Ichi Takeyama,
Hiroshi Shibuya, Fumiaki Ohtake,
Shigeaki Kato
Nature 06/2012; 486(7402):280. · 36.28 Impact Factor
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ABSTRACT: Osteoclastogenesis is a highly regulated process governed by diverse classes of regulators. Among them, nuclear factor of activated T-cells calcineurin-dependent 1 (NFATc1) is the primary osteoclastogenic transcription factor, and its expression is transcriptionally induced during early osteoclastogenesis by receptor activation of nuclear factor κB ligand (RANKL), an osteoclastogenic cytokine. Here, we report the novel enzymatic function of JMJD5, which regulates NFATc1 protein stability. Among the tested Jumonji C (JmjC) domain-containing proteins, decreased mRNA expression levels during osteoclastogenesis were found for JMJD5 in RAW264 cells stimulated by RANKL. To examine the functional role of JMJD5 in osteoclast differentiation, we established stable JMJD5 knockdown cells, and osteoclast formation was assessed. Down-regulated expression of JMJD5 led to accelerated osteoclast formation together with induction of several osteoclast-specific genes such as Ctsk and DC-STAMP, suggesting that JMJD5 is a negative regulator in osteoclast differentiation. Although JMJD5 was recently reported as a histone demethylase for histone H3K36me2, no histone demethylase activity was detected in JMJD5 in vitro or in living cells, even for other methylated histone residues. Instead, JMJD5 co-repressed transcriptional activity by destabilizing NFATc1 protein. Protein hydroxylase activity mediated by the JmjC domain in JMJD5 was required for the observed functions of JMJD5. JMJD5 induced the association of hydroxylated NFATc1 with the E3 ubiquitin ligase Von Hippel-Lindau tumor suppressor (VHL), thereby presumably facilitating proteasomal degradation of NFATc1 via ubiquitination. Taken together, the present study demonstrated that JMJD5 is a post-translational co-repressor for NFATc1 that attenuates osteoclastogenesis.
Journal of Biological Chemistry 02/2012; 287(16):12994-3004. · 4.77 Impact Factor
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Saya Ito,
Sally Fujiyama-Nakamura,
Shuhei Kimura,
Jinseon Lim,
Yuki Kamoshida,
Yumi Shiozaki-Sato,
Shun Sawatsubashi,
Eriko Suzuki,
Masahiko Tanabe,
Takashi Ueda,
Takuya Murata,
Hiromi Kato, Fumiaki Ohtake,
Ryoji Fujiki,
Tsuneharu Miki,
Alexander Kouzmenko,
Ken-Ichi Takeyama,
Shigeaki Kato
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ABSTRACT: Cell cycle-dependent expression of canonical histone proteins enables newly synthesized DNA to be integrated into chromatin in replicating cells. However, the molecular basis of cell cycle-dependency in the switching of histone gene regulation remains to be uncovered. Here, we report the identification and biochemical characterization of a molecular switcher, HERS (histone gene-specific epigenetic repressor in late S phase), for nucleosomal core histone gene inactivation in Drosophila. HERS protein is phosphorylated by a cyclin-dependent kinase (Cdk) at the end of S-phase. Phosphorylated HERS binds to histone gene regulatory regions and anchors HP1 and Su(var)3-9 to induce chromatin inactivation through histone H3 lysine 9 methylation. These findings illustrate a salient molecular switch linking epigenetic gene silencing to cell cycle-dependent histone production.
Molecular cell 02/2012; 45(4):494-504. · 14.61 Impact Factor
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Ryoji Fujiki,
Waka Hashiba,
Hiroki Sekine,
Atsushi Yokoyama,
Toshihiro Chikanishi,
Saya Ito,
Yuuki Imai,
Jaehoon Kim,
Housheng Hansen He,
Katsuhide Igarashi,
Jun Kanno, Fumiaki Ohtake,
Hirochika Kitagawa,
Robert G Roeder,
Myles Brown,
Shigeaki Kato
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ABSTRACT: Chromatin reorganization is governed by multiple post-translational modifications of chromosomal proteins and DNA. These histone modifications are reversible, dynamic events that can regulate DNA-driven cellular processes. However, the molecular mechanisms that coordinate histone modification patterns remain largely unknown. In metazoans, reversible protein modification by O-linked N-acetylglucosamine (GlcNAc) is catalysed by two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). However, the significance of GlcNAcylation in chromatin reorganization remains elusive. Here we report that histone H2B is GlcNAcylated at residue S112 by OGT in vitro and in living cells. Histone GlcNAcylation fluctuated in response to extracellular glucose through the hexosamine biosynthesis pathway (HBP). H2B S112 GlcNAcylation promotes K120 monoubiquitination, in which the GlcNAc moiety can serve as an anchor for a histone H2B ubiquitin ligase. H2B S112 GlcNAc was localized to euchromatic areas on fly polytene chromosomes. In a genome-wide analysis, H2B S112 GlcNAcylation sites were observed widely distributed over chromosomes including transcribed gene loci, with some sites co-localizing with H2B K120 monoubiquitination. These findings suggest that H2B S112 GlcNAcylation is a histone modification that facilitates H2BK120 monoubiquitination, presumably for transcriptional activation.
Nature 11/2011; 480(7378):557-60. · 36.28 Impact Factor
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Mi-Sun Kim,
Takeshi Kondo,
Ichiro Takada,
Min-Young Youn,
Yoko Yamamoto,
Sayuri Takahashi,
Takahiro Matsumoto,
Sally Fujiyama,
Yuko Shirode,
Ikuko Yamaoka,
Hirochika Kitagawa,
Ken-ichi Takeyama,
Hiroshi Shibuya, Fumiaki Ohtake,
Shigeaki Kato
Nature 10/2011; · 36.28 Impact Factor
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Atsushi Baba, Fumiaki Ohtake,
Yosuke Okuno,
Kenichi Yokota,
Maiko Okada,
Yuuki Imai,
Min Ni,
Clifford A Meyer,
Katsuhide Igarashi,
Jun Kanno,
Myles Brown,
Shigeaki Kato
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ABSTRACT: Reversible histone methylation and demethylation are highly regulated processes that are crucial for chromatin reorganization and regulation of gene transcription in response to extracellular conditions. However, the mechanisms that regulate histone-modifying enzymes are largely unknown. Here, we characterized a protein kinase A (PKA)-dependent histone lysine demethylase complex, PHF2-ARID5B. PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. This modification leads to targeting of the PHF2-ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. These findings suggest that the PHF2-ARID5B complex is a signal-sensing modulator of histone methylation and gene transcription, in which phosphorylation of PHF2 enables subsequent formation of a competent and specific histone demethylase complex.
Nature Cell Biology 06/2011; 13(6):668-75. · 19.49 Impact Factor
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ABSTRACT: The arylhydrocarbon receptor (AhR) is a ligand-dependent transcription factor mediating the adverse effects of dioxins. Although cross-talk of dioxins with estrogen and androgen signaling pathways are well described, the underlying molecular mechanisms have been largely elusive. Recent studies showed that modulation of estrogen/androgen signaling by dioxins is exerted in part through direct association of AhR with estrogen (ER) or androgen (AR) receptors. Agonist-bound AhR and ERα work as a functional unit to regulate expression of target genes. In addition to such genomic actions, AhR mediates non-genomic actions of AhR-ligands through the assembly of a CUL4B-based ubiquitin ligase complex and promotes the degradation of ERα and AR. These findings reveal the roles of the ubiquitin system in sensing and biological response to environmental chemicals, in which AhR acts as a ubiquitin ligase component to enhance the destruction of specific substrates.
The Journal of steroid biochemistry and molecular biology 03/2011; 127(1-2):102-7. · 2.66 Impact Factor
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ABSTRACT: Methylation and demethylation of cytosine residues in the genomic DNA play key roles in a wide range of fundamental biological processes such as differentiation and development, genome stability, imprinting, X chromosome inactivation, carcinogenesis and aging. DNA methylation is considered to be a stable modification associated with the epigenetic silencing of genomic loci and maintained through cellular division. Recent studies however, suggest that DNA methylation and demethylation are considerably more dynamic than previously thought and may be involved in repression and derepression of gene activity during the lifespan of a cell. This article is focused on epigenetic mechanisms in the hormonal regulation of the cytochrome p450 27B1 or CYP27B1 gene activity that involve reversible epigenetic modifications to chromatin and DNA methylation profiles.
Epigenomics 12/2010; 2(6):765-74.
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Mi-Sun Kim,
Takeshi Kondo,
Ichiro Takada,
Min-Young Youn,
Yoko Yamamoto,
Sayuri Takahashi,
Takahiro Matsumoto,
Sally Fujiyama,
Yuko Shirode,
Ikuko Yamaoka,
Hirochika Kitagawa,
Ken-ichi Takeyama,
Hiroshi Shibuya, Fumiaki Ohtake,
Shigeaki Kato
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ABSTRACT: Epigenetic modifications at the histone level affect gene regulation in response to extracellular signals. However, regulated epigenetic modifications at the DNA level, especially active DNA demethylation, in gene activation are not well understood. Here we report that DNA methylation/demethylation is hormonally switched to control transcription of the cytochrome p450 27B1 (CYP27B1) gene. Reflecting vitamin-D-mediated transrepression of the CYP27B1 gene by the negative vitamin D response element (nVDRE), methylation of CpG sites ((5m)CpG) is induced by vitamin D in this gene promoter. Conversely, treatment with parathyroid hormone, a hormone known to activate the CYP27B1 gene, induces active demethylation of the (5m)CpG sites in this promoter. Biochemical purification of a complex associated with the nVDRE-binding protein (VDIR, also known as TCF3) identified two DNA methyltransferases, DNMT1 and DNMT3B, for methylation of CpG sites, as well as a DNA glycosylase, MBD4 (ref. 10). Protein-kinase-C-phosphorylated MBD4 by parathyroid hormone stimulation promotes incision of methylated DNA through glycosylase activity, and a base-excision repair process seems to complete DNA demethylation in the MBD4-bound promoter. Such parathyroid-hormone-induced DNA demethylation and subsequent transcriptional derepression are impaired in Mbd4(-/-) mice. Thus, the present findings suggest that methylation switching at the DNA level contributes to the hormonal control of transcription.
Nature 10/2009; 461(7266):1007-12. · 36.28 Impact Factor
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Kaname Kawajiri,
Yasuhito Kobayashi, Fumiaki Ohtake,
Togo Ikuta,
Yoshibumi Matsushima,
Junsei Mimura,
Sven Pettersson,
Richard S Pollenz,
Toshiyuki Sakaki,
Takatsugu Hirokawa,
Tetsu Akiyama,
Masafumi Kurosumi,
Lorenz Poellinger,
Shigeaki Kato,
Yoshiaki Fujii-Kuriyama
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ABSTRACT: Intestinal cancer is one of the most common human cancers. Aberrant activation of the canonical Wnt signaling cascade, for example, caused by adenomatous polyposis coli (APC) gene mutations, leads to increased stabilization and accumulation of beta-catenin, resulting in initiation of intestinal carcinogenesis. The aryl hydrocarbon receptor (AhR) has dual roles in regulating intracellular protein levels both as a ligand-activated transcription factor and as a ligand-dependent E3 ubiquitin ligase. Here, we show that the AhR E3 ubiquitin ligase has a role in suppression of intestinal carcinogenesis by a previously undescribed ligand-dependent beta-catenin degradation pathway that is independent of and parallel to the APC system. This function of AhR is activated by both xenobiotics and natural AhR ligands, such as indole derivatives that are converted from dietary tryptophan and glucosinolates by intestinal microbes, and suppresses intestinal tumor development in Apc(Min/+) mice. These findings suggest that chemoprevention with naturally-occurring and chemically-designed AhR ligands can be used to successfully prevent intestinal cancers.
Proceedings of the National Academy of Sciences 08/2009; 106(32):13481-6. · 9.68 Impact Factor
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ABSTRACT: The arylhydrocarbon receptor (AhR) mediates the adverse effects of dioxins, including modulation of sex steroid hormone signaling. The role of AhR as a transcription factor is well described. AhR regulates the expression of target genes such as CYP1A1; however, the mechanisms of AhR function through other target-selective systems remain elusive. Accumulating evidence suggests that AhR modulates the functions of other transcription factors. The ligand-activated AhR directly associates with estrogen or androgen receptors (ERalpha or AR) and modulates their function both positively and negatively. This may, in part explain the sex steroid hormone-related adverse effects of dioxins. AhR has recently been shown to promote the proteolysis of ERalpha/AR through assembling a ubiquitin ligase complex, CUL4B(AhR). In the CUL4B(AhR) complex, AhR acts as a substrate-recognition subunit to recruit ERalpha/AR. This action defines a novel role for AhR as a ligand-dependent E3 ubiquitin ligase. We propose that target-specific regulation of protein destruction, as well as gene expression, is modulated by environmental toxins through the E3 ubiquitin ligase activity of AhR.
Biochemical pharmacology 10/2008; 77(4):474-84. · 4.25 Impact Factor
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ABSTRACT: The arylhydrocarbon receptor (AhR) mediates sex steroid hormone-related actions in both normal physiology and in dioxin toxicity. In addition to regulation of direct target genes, the ligand-activated AhR associates with estrogen or androgen receptors (ERalpha or AR) to regulate transcription as a functional unit. Given that endogenous and exogenous AhR-ligands are structurally diverse, it is unclear whether cross-talk regulation of ERalpha/AR by the activated AhR is an intrinsic function of the AhR or the result of ligand-type-selective differences. To ensure uniform activity of the AhR irrespective of ligand-type-specific differences, we employed CA-AhR, which lacks the ligand-binding domain and has a constitutive activity. We found that CA-AhR, in the absence of a ligand, acted as a transcriptional co-regulator for the unliganded ERalpha/AR as well as for mutants of ERalpha/AR lacking a ligand-binding domain. CA-AhR was recruited to estrogen-/androgen-responsive promoters with endogenous ERalpha/AR. Moreover, CA-AhR had an E3 ubiquitin ligase activity and promoted proteasomal degradation of ERalpha/AR. Thus, these findings indicate that the cross-talk function of the AhR with sex hormone receptors is an intrinsic function of the AhR.
Biochemical and Biophysical Research Communications 07/2008; 370(4):541-6. · 2.48 Impact Factor
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Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 01/2008; 52(15):1973-9.
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Ichiro Takada,
Masatomo Mihara,
Miyuki Suzawa, Fumiaki Ohtake,
Shinji Kobayashi,
Mamoru Igarashi,
Min-Young Youn,
Ken-ichi Takeyama,
Takashi Nakamura,
Yoshihiro Mezaki,
Shinichiro Takezawa,
Yoshiko Yogiashi,
Hirochika Kitagawa,
Gen Yamada,
Shinji Takada,
Yasuhiro Minami,
Hiroshi Shibuya,
Kunihiro Matsumoto,
Shigeaki Kato
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ABSTRACT: Histone modifications induced by activated signalling cascades are crucial to cell-lineage decisions. Osteoblast and adipocyte differentiation from common mesenchymal stem cells is under transcriptional control by numerous factors. Although PPAR-gamma (peroxisome proliferator activated receptor-gamma) has been established as a prime inducer of adipogenesis, cellular signalling factors that determine cell lineage in bone marrow remain generally unknown. Here, we show that the non-canonical Wnt pathway through CaMKII-TAK1-TAB2-NLK transcriptionally represses PPAR-gamma transactivation and induces Runx2 expression, promoting osteoblastogenesis in preference to adipogenesis in bone marrow mesenchymal progenitors. Wnt-5a activates NLK (Nemo-like kinase), which in turn phosphorylates a histone methyltransferase, SETDB1 (SET domain bifurcated 1), leading to the formation of a co-repressor complex that inactivates PPAR-gamma function through histone H3-K9 methylation. These findings suggest that the non-canonical Wnt signalling pathway suppresses PPAR-gamma function through chromatin inactivation triggered by recruitment of a repressing histone methyltransferase, thus leading to an osteoblastic cell lineage from mesenchymal stem cells.
Nature Cell Biology 12/2007; 9(11):1273-85. · 19.49 Impact Factor
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Fumiaki Ohtake,
Atsushi Baba,
Ichiro Takada,
Maiko Okada,
Kei Iwasaki,
Hiromi Miki,
Sayuri Takahashi,
Alexander Kouzmenko,
Keiko Nohara,
Tomoki Chiba,
Yoshiaki Fujii-Kuriyama,
Shigeaki Kato
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ABSTRACT: Fat-soluble ligands, including sex steroid hormones and environmental toxins, activate ligand-dependent DNA-sequence-specific transcriptional factors that transduce signals through target-gene-selective transcriptional regulation. However, the mechanisms of cellular perception of fat-soluble ligand signals through other target-selective systems remain unclear. The ubiquitin-proteasome system regulates selective protein degradation, in which the E3 ubiquitin ligases determine target specificity. Here we characterize a fat-soluble ligand-dependent ubiquitin ligase complex in human cell lines, in which dioxin receptor (AhR) is integrated as a component of a novel cullin 4B ubiquitin ligase complex, CUL4B(AhR). Complex assembly and ubiquitin ligase activity of CUL4B(AhR) in vitro and in vivo are dependent on the AhR ligand. In the CUL4B(AhR) complex, ligand-activated AhR acts as a substrate-specific adaptor component that targets sex steroid receptors for degradation. Thus, our findings uncover a function for AhR as an atypical component of the ubiquitin ligase complex and demonstrate a non-genomic signalling pathway in which fat-soluble ligands regulate target-protein-selective degradation through a ubiquitin ligase complex.
Nature 04/2007; 446(7135):562-6. · 36.28 Impact Factor
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ABSTRACT: The development of reproductive organ tumors such as breast and prostate cancer often depends on the action of sex hormones. Nuclear sex hormone receptors are members of the nuclear hormone receptor superfamily and act as ligand-inducible transcription factors, controlling the expression of target genes. Nuclear receptors are considered to directly and indirectly interact with a number of nuclear co-regulatory complexes involved in chromatin remodeling and histone modification. Moreover, many intracellular signalings via cell membrane receptors are shown to modulate nuclear receptor-regulated transcription. We have shown that estrogen receptors (ER) associate with a number of nuclear complexes, one of which is a spliceosome complex. We recently found that this spliceosome complex interacts with phosphorylated ER by MAP kinase, generating a novel cross-talk of estrogen and growth factor signalings. We also observed that a dioxin receptor (AhR) is capable of associating with ER, resulting in modulation of ER transactivation function. From our findings we believe that development of estrogen-dependent breast cancer may be mediated through the other signaling pathways. To address the function of the androgen receptor (AR) in androgen-dependent prostate cancer, we established a transgenic mouse line expressing a human AR mutant that is found in androgen-independent prostate cancer patients. The hAR mutant mice, generated through a Cre-loxP system, developed hyperplasia in the prostates. Hypersensitivity of AR mutants to antagonists and endogenous steroid hormones may potentiate hormone-dependency in prostate cancer development.
Cancer Chemotherapy and Pharmacology 12/2005; 56 Suppl 1:4-9. · 2.83 Impact Factor
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Fumiaki Ohtake,
Ken-ichi Takeyama,
Takahiro Matsumoto,
Hirochika Kitagawa,
Yasuji Yamamoto,
Keiko Nohara,
Chiharu Tohyama,
Andree Krust,
Junsei Mimura,
Pierre Chambon,
Junn Yanagisawa,
Yoshiaki Fujii-Kuriyama,
Shigeaki Kato
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ABSTRACT: Environmental contaminants affect a wide variety of biological events in many species. Dioxins are typical environmental contaminants that exert adverse oestrogen-related effects. Although their anti-oestrogenic actions are well described, dioxins can also induce endometriosis and oestrogen-dependent tumours, implying possible oestrogenic effects. However, the molecular mechanism underlying oestrogen-related actions of dioxins remains largely unknown. A heterodimer of the dioxin receptor (AhR) and Arnt, which are basic helix-loop-helix/PAS-family transcription factors, mediates most of the toxic effects of dioxins. Here we show that the agonist-activated AhR/Arnt heterodimer directly associates with oestrogen receptors ER-alpha and ER-beta. This association results in the recruitment of unliganded ER and the co-activator p300 to oestrogen-responsive gene promoters, leading to activation of transcription and oestrogenic effects. The function of liganded ER is attenuated. Oestrogenic actions of AhR agonists were detected in wild-type ovariectomized mouse uteri, but were absent in AhR-/- or ER-alpha-/- ovariectomized mice. Our findings suggest a novel mechanism by which ER-mediated oestrogen signalling is modulated by a co-regulatory-like function of activated AhR/Arnt, giving rise to adverse oestrogen-related actions of dioxin-type environmental contaminants.
Nature 06/2003; 423(6939):545-50. · 36.28 Impact Factor
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Miyuki Suzawa,
Ichiro Takada,
Junn Yanagisawa, Fumiaki Ohtake,
Satoko Ogawa,
Toshimasa Yamauchi,
Takashi Kadowaki,
Yasuhiro Takeuchi,
Hiroshi Shibuya,
Yukiko Gotoh,
Kunihiro Matsumoto,
Shigeaki Kato
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ABSTRACT: Pluripotent mesenchymal stem cells in bone marrow differentiate into adipocytes, osteoblasts and other cells. Balanced cytodifferentiation of stem cells is essential for the formation and maintenance of bone marrow; however, the mechanisms that control this balance remain largely unknown. Whereas cytokines such as interleukin-1 (IL-1) and tumour-necrosis factor-alpha (TNF-alpha) inhibit adipogenesis, the ligand-induced transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma), is a key inducer of adipogenesis. Therefore, regulatory coupling between cytokine- and PPAR-gamma-mediated signals might occur during adipogenesis. Here we show that the ligand-induced transactivation function of PPAR-gamma is suppressed by IL-1 and TNF-alpha, and that this suppression is mediated through NF-kappaB activated by the TAK1/TAB1/NF-kappaB-inducing kinase (NIK) cascade, a downstream cascade associated with IL-1 and TNF-alpha signalling. Unlike suppression of the PPAR-gamma transactivation function by mitogen-activated protein kinase-induced growth factor signalling through phosphorylation of the A/B domain, NF-kappaB blocks PPAR-gamma binding to DNA by forming a complex with PPAR-gamma and its AF-1-specific co-activator PGC-2. Our results suggest that expression of IL-1 and TNF-alpha in bone marrow may alter the fate of pluripotent mesenchymal stem cells, directing cellular differentiation towards osteoblasts rather than adipocytes by suppressing PPAR-gamma function through NF-kappaB activated by the TAK1/TAB1/NIK cascade.
Nature Cell Biology 04/2003; 5(3):224-30. · 19.49 Impact Factor
