Nuclear receptors: action, functions, and roles in disease

核受体:在疾病中的作用、功能和作用

基本信息

项目摘要

I. RORalpha and gamma: The retinoid-related orphan receptor a and g (RORa and RORg) are members of the nuclear receptor superfamily. To identify the physiological functions of RORa and g, mice deficient in RORa and g function were analyzed. RORg exhibit several functions in the immune system. RORg expression is indispensable for lymph node organogenesis and plays a critical role in thymocyte homeostasis. Recently a role for RORg in Th17 cell differentiation was identified. We demonstrated that both RORa and RORg are induced during Th17 cells differentiation and double knockouts mice are resistant to experimental autoimmune encephalomyelitis, a model for multiple sclerosis. In addition, RORg-deficient mice are less susceptible to aovalbumin (OVA)-induced inflammation in mice, a model for allergic airway disease. Retinoid-related orphan receptors alpha (RORa) and gamma (RORg) are both expressed in liver; however, their physiological functions in this tissue have not yet been clearly defined. RORa1 and RORg1 show an oscillatory pattern of expression during circadian rhythm. Comparison of gene expression profiles of livers from WT, RORa-deficient staggerer mice (RORasg/sg), RORg-/-, and RORasg/sgRORg-/- double knockout (DKO) mice by microarray analysis demonstrated that RORa and RORg are particularly important in the regulation of genes encoding several Phase I and Phase II metabolic enzymes, including several 3b-hydroxysteroid dehydrogenases (Hsd3b), cytochrome P450 (Cyp) enzymes, and sulfotransferases. In addition, our results indicate that RORa and RORg each affect the expression of a specific set of genes but also exhibit functional redundancy. Our study shows that RORa and RORg receptors influence the regulation of several metabolic pathways, including those involved in the metabolism of steroids, bile acids, and xenobiotics, suggesting that RORs are important in the control of metabolic homeostasis. RORa plays an important role in the regulation of energy homeostasis. Mice deficient in RORa are resistant to diet-induced obesity and reduced inflammation in adipose tissue. A number of lipogenic genes were identified that are positively regulated by RORa. Because RORs function as ligand-dependent transcription factors, RORa might be a therapeutic target for the management of obesity. RORg was found to play an important role in the circadian regulation of several genes downstream of the circadian clock. Our studies further demonstrated that Prox1 interacts with ROR nuclear receptors and represses the transcriptional activity of RORγ and expression of RORγ, thereby contributing to the down-regulation of several ROR target genes. The AF2 in the LBD of RORs and the homeo/propero-like domain of Prox1 are required for the interaction as well as repression. Our study identifies Prox1 as a novel modulator of ROR transcriptional regulation and as such is an integral part of the circadian clock and metabolic regulatory networks. II. TAK1: The nuclear orphan receptor TAK1 functions as a positive as well as a negative regulator of transcription; however little is know about factors mediating its activity. Yeast two-hybrid analysis using the ligand binding domain of TAK1 as bait identified a novel TAK1-interacting protein, referred to as TIP27. Our studies indicate that TIP27 is an effective repressor of transcriptional activation by TAK1 and, therefore, may play a critical role in the regulation of several physiological functions by TAK1. Generation of TAK1 knockout mice revealed several phenotypes that are currently being investigated. TAK1-deficient (TAK1-/-) mice and report that these mice exhibit a smaller cerebellum and deficit in foliation of lobules VI-VII. The absence of TAK1 results in a coordinated deficit in cerebellar granule neurons, Purkinje cells, and radial glia during development altering long-term neurobehavioral functioning. These data indicate that TAK1 is an important transcriptional modulator of neurodevelopmentally-regulated behavior. In addition, we found that TAK1 plays a role in the regulation of energy homeostasis. Mice deficient in TAK1 are protected against the development of obesity,hepatic steatosis,and insulin resistance. A number of lipogenic genes were identified that are positively regulated by TAK1. III. Receptor associated protein (RAP80), a nuclear protein containing two ubiquitin-interacting motifs (UIMs), interacts with the esstrogen receptor alpha (ERa) in an agonist dependent manner. In addition, RAP80 is implicated in DNA repair and is associated with the tumor suppressor Breast cancer-1 (BRCA1) protein complex and mediates BRCA1 translocation to sites of DNA damage. We showed that this translocation is dependent on the UIMs of RAP80. We demonstrated that the ataxia-telangiectasia mutated protein kinase (ATM) can phosphorylate RAP80 in vitro at Ser205. Using an anti-RAP80Ser205P antibody that specifically recognizes RAP80 phosphorylated at Ser205 we demonstrated that RAP80Ser205P translocates to sites of DNA damage. We show that this phosphorylation is mediated by ATM and does not require a functional BRCA1. Ultraviolet (UV) irradiation also induces translocation of RAP80 to DNA damage foci that co-localize with γ-H2AX. We further show that this translocation is also dependent on the UIMs of RAP80 and that the UV-induced phosphorylation of RAP80 at Ser205 is mediated by ATR, not ATM. Our findings suggest that RAP80 has a more general role in different types of DNA damage response signaling pathways. Using genomic and functional analysis we established that the expression of the RAP80 gene is regulated in a DNA damage-responsive manner by the master regulator p53. This regulation occurs at the transcriptional level through a noncanonical p53 response element in the RAP80 promoter. While it is inducible by p53, RAP80 is also able to regulate p53 through an association with both p53 and the E3 ubiquitin ligase HDM2, providing HDM2-dependent enhancement of p53 polyubiquitination. Thus, we provide evidence that RAP80 can function in an autoregulatory loop consisting of RAP80, HDM2 and the p53 master regulatory network, implying an important role for this loop in genome stability and oncogenesis. RAP80 knockout mice were generated to determine the effect of loss of RAP80 on DNA stability and susceptibility to cancer. . RAP80-/- mice were more susceptible to spontaneous lymphoma development and the development of DMBA-induced mammary gland tumors. Moreover, the loss of RAP80 accelerated tumor formation in both p53-/- and p53+/- mice. Our data indicate that RAP80-deficiency promotes genomic instability and causes an increase in cancer risk consistent with the concept that RAP80 exhibits a tumor suppressor function. III. Our studies further demonstrate that mice deficient in CD44 are considerably resistant to diet-induced hepatic steatosis, fibrogenesis, and inflammation, adipose-associated infiltration of M1 macrophages, glucose intolerance, and insulin resistance. These observations suggest that CD44 provides a critical link between metabolic changes and the development of inflammation and insulin resistance. Because CD44 functions as a receptor, it may provide a convenient therapeutic target in the management of lipid dysregulation in diet-induced liver disease and type 2 diabetes.
r α和γ:类维甲酸相关孤儿受体a和g (RORa和RORg)是核受体超家族的成员。为了确定RORa和g的生理功能,我们对RORa和g功能缺失的小鼠进行了分析。RORg在免疫系统中表现出几种功能。RORg的表达在淋巴结器官形成中不可或缺,在胸腺细胞稳态中起着关键作用。最近发现了RORg在Th17细胞分化中的作用。我们证明,在Th17细胞分化过程中,RORa和RORg都被诱导,双敲除小鼠对实验性自身免疫性脑脊髓炎(多发性硬化症的一种模型)具有抗性。此外,rorg缺陷小鼠对卵清蛋白(OVA)诱导的小鼠炎症(过敏性气道疾病模型)不太敏感。

项目成果

期刊论文数量(0)
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Anton M Jetten其他文献

化学物質と核内受容体:毒性評価・環境測定・創薬への展開
化学物质和核受体:毒性评估、环境测量和药物发现的进展
  • DOI:
  • 发表时间:
    2015
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Hiroyuki Kojima;Yukimasa Takeda;Ryuta Muromoto;Miki Takahashi;Toru Hirao;Shinji Takeuchi;Anton M Jetten;and Tadashi Matsuda;小島弘幸
  • 通讯作者:
    小島弘幸
Promoting healthy aging. A 10-year community intervention for frailty prevention and its impact upon healthy aging in Japan
促进健康老龄化。
  • DOI:
  • 发表时间:
    2014
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Hiroyuki Kojima;Yukimasa Takeda;Ryuta Muromoto;Miki Takahashi;Toru Hirao;Shinji Takeuchi;Anton M Jetten;and Tadashi Matsuda;Shinkai S
  • 通讯作者:
    Shinkai S
Vasodilatory properties of ghlerin in the rat
大鼠中ghlerin的血管舒张特性
  • DOI:
  • 发表时间:
    2014
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Hiroyuki Kojima;Yukimasa Takeda;Ryuta Muromoto;Miki Takahashi;Toru Hirao;Shinji Takeuchi;Anton M Jetten;and Tadashi Matsuda;M. Ishido
  • 通讯作者:
    M. Ishido
In vitro endocrine-disrupting effects of pesticides via nuclear receptors.
农药通过核受体的体外内分泌干扰作用。
  • DOI:
  • 发表时间:
    2014
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Hiroyuki Kojima;Yukimasa Takeda;Ryuta Muromoto;Miki Takahashi;Toru Hirao;Shinji Takeuchi;Anton M Jetten;and Tadashi Matsuda;小島弘幸;Hiroyuki Kojima
  • 通讯作者:
    Hiroyuki Kojima

Anton M Jetten的其他文献

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{{ truncateString('Anton M Jetten', 18)}}的其他基金

REGULATION OF DIFFERENTIATION IN LUNG AND EPIDERMAL KERATINOCYTES
肺和表皮角质形成细胞分化的调节
  • 批准号:
    6289934
  • 财政年份:
  • 资助金额:
    $ 119.77万
  • 项目类别:
Functions of PPAR in the lung
PPAR 在肺中的功能
  • 批准号:
    6673284
  • 财政年份:
  • 资助金额:
    $ 119.77万
  • 项目类别:
Nuclear receptors: action, functions, and roles in disea
核受体:在疾病中的作用、功能和作用
  • 批准号:
    7327214
  • 财政年份:
  • 资助金额:
    $ 119.77万
  • 项目类别:
Nuclear receptors: action, functions, and roles in disease
核受体:在疾病中的作用、功能和作用
  • 批准号:
    8336619
  • 财政年份:
  • 资助金额:
    $ 119.77万
  • 项目类别:
Regulation Of Differentiation In Lung Keratinocytes
肺角质形成细胞分化的调节
  • 批准号:
    7007108
  • 财政年份:
  • 资助金额:
    $ 119.77万
  • 项目类别:
Mechanism Of Action And Functions Of Glis 1-3
Glis的作用机制和功能1-3
  • 批准号:
    7007508
  • 财政年份:
  • 资助金额:
    $ 119.77万
  • 项目类别:
Mechanism Of Action And Functions Of The Gli-related Proteins Glis 1-3
Gli相关蛋白Glis 1-3的作用机制和功能
  • 批准号:
    7968157
  • 财政年份:
  • 资助金额:
    $ 119.77万
  • 项目类别:
Mechanism Of Action And Functions Of The Gli-related Proteins Glis 1-3
Gli相关蛋白Glis 1-3的作用机制和功能
  • 批准号:
    8149074
  • 财政年份:
  • 资助金额:
    $ 119.77万
  • 项目类别:
FUNCTION AND ACTION OF NUCLEAR RECEPTOR RORGAMMA
核受体 RORGAMMA 的功能和作用
  • 批准号:
    6289935
  • 财政年份:
  • 资助金额:
    $ 119.77万
  • 项目类别:
Regulation Of Differentiation In Lung And Epidermal Kera
肺和表皮角质层分化的调节
  • 批准号:
    6837504
  • 财政年份:
  • 资助金额:
    $ 119.77万
  • 项目类别:

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