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: 7734528
• 负责人: Anton M Jetten
• 金额: $ 151.08万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7734528
• 关键词: Adult; Affect; Agonist; Amino Acid Motifs; Antibodies; Asthma; Ataxia-Telangiectasia-Mutated protein kinase; Autoimmune Diseases; Bile Acids; Cell Differentiation process; Circadian Rhythms; Complex; Cytochrome P450; DNA Damage; DNA Repair; Development, Other; Disease; Embryonic Development; Enzymes; Estrogen Receptor 1; Estrogen Receptor alpha; Exhibits; Experimental Autoimmune Encephalomyelitis; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic Transcription; Homeostasis; Hydroxysteroid Dehydrogenases; Immune response; Immune system; In Vitro; Inflammation; Inflammatory; Ionizing radiation; Knockout Mice; Ligand Binding Domain; Ligands; Liver; Localized; MAP3K7 gene; Malignant Neoplasms; Mediating; Metabolic; Metabolic Control; Metabolic Pathway; Metabolic syndrome; Microarray Analysis; Modeling; Molecular Profiling; Multiple Sclerosis; Mus; Nuclear Orphan Receptor; Nuclear Protein; Nuclear Proteins; Nuclear Receptors; Obesity; Organogenesis; Orphan; Osteogenesis; Pattern; Phase; Phenotype; Phosphorylation; Physiological; Physiological Processes; Play; Proteins; Regulation; Resistance; Retinoids; Risk; Role; Signal Pathway; Signal Transduction; Site; Staggerer Mouse; Tissues; Transcriptional Activation; Tumor Suppressor Proteins; Ubiquitin; Xenobiotics; Yeasts; allergic airway disease; human disease; insight; irradiation; lipid metabolism; lymph nodes; malignant breast neoplasm; member; mutant; novel; receptor; receptor function; response; steroid metabolism; sulfotransferase; thymocyte; transcription factor; ultraviolet; ultraviolet irradiation; yeast two hybrid system

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. 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. 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. This interaction is mediated through the BRCT repeats of BRCA1. RAP80 translocates to ionizing radiation-induced foci (IRIF) and mediate BRCA1 translocation to IRIfs. We showed that this translocation is dependent on the UIMs of RAP80. We demonstrated that the BRCT mutant of BRCA1, R1699W, which is associated with increased risk of breast cancer, is unable to interact with RAP80. 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 IRIF. We show that this phosphorylation is mediated by ATM and does not require a functional BRCA1. The phosphorylation occurs within 5 min after irradiation. 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.

I. RORα 和γ：类维生素A 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，对 RORa 和 g 功能缺陷的小鼠进行了分析。 RORg 在免疫系统中表现出多种功能。 RORg 表达对于淋巴结器官发生是不可或缺的，并且在胸腺细胞稳态中发挥关键作用。 最近确定了 RORg 在 Th17 细胞分化中的作用。我们证明了 RORa 和 RORg 在 Th17 细胞分化过程中被诱导，并且双基因敲除小鼠对实验性自身免疫性脑脊髓炎（多发性硬化症模型）具有抵抗力。此外，RORg 缺陷小鼠对卵清蛋白 (OVA) 诱导的小鼠炎症不太敏感，小鼠是过敏性气道疾病的模型。 类维生素A相关孤儿受体α（RORa）和γ（RORg）均在肝脏中表达；然而，它们在该组织中的生理功能尚未明确定义。 RORa1 和 RORg1 在昼夜节律期间表现出振荡表达模式。通过微阵列分析比较 WT、RORa 缺陷交错小鼠 (RORasg/sg)、RORg-/- 和 RORasg/sgRORg-/- 双敲除 (DKO) 小鼠肝脏的基因表达谱，表明 RORa 和 RORg 特别重要参与编码多种 I 期和 II 期代谢酶的基因的调节，包括几种 3b-羟基类固醇脱氢酶 (Hsd3b)、细胞色素P450 (Cyp) 酶和磺基转移酶。此外，我们的结果表明，RORa 和 RORg 各自影响一组特定基因的表达，但也表现出功能冗余。我们的研究表明，RORa 和 RORg 受体影响多种代谢途径的调节，包括参与类固醇、胆汁酸和异生物质代谢的途径，这表明 ROR 在控制代谢稳态中很重要。 二. TAK1：核孤儿受体 TAK1 充当转录的正调节因子和负调节因子；然而，人们对调节其活动的因素知之甚少。使用 TAK1 的配体结合域作为诱饵进行酵母双杂交分析，鉴定出一种新型 TAK1 相互作用蛋白，称为 TIP27。我们的研究表明，TIP27 是 TAK1 转录激活的有效抑制因子，因此可能在 TAK1 多种生理功能的调节中发挥关键作用。 TAK1 敲除小鼠的产生揭示了目前正在研究的几种表型。 三．受体相关蛋白 (RAP80) 是一种含有两个泛素相互作用基序 (UIM) 的核蛋白，以激动剂依赖性方式与雌激素受体 α (ERa) 相互作用。此外，RAP80 参与 DNA 修复，并与肿瘤抑制乳腺癌 1 (BRCA1) 蛋白复合物相关。这种相互作用是通过 BRCA1 的 BRCT 重复序列介导的。 RAP80 易位至电离辐射诱导灶 (IRIF) 并介导 BRCA1 易位至 IRIf。我们表明这种易位依赖于 RAP80 的 UIM。我们证明，与乳腺癌风险增加相关的 BRCA1 的 BRCT 突变体 R1699W 无法与 RAP80 相互作用。共济失调毛细血管扩张突变蛋白激酶 (ATM) 可在体外磷酸化 RAP80 Ser205。使用特异性识别 Ser205 磷酸化 RAP80 的抗 RAP80Ser205P 抗体，我们证明 RAP80Ser205P 易位至 IRIF。我们证明这种磷酸化是由 ATM 介导的，不需要功能性 BRCA1。磷酸化在照射后 5 分钟内发生。紫外线 (UV) 照射还会诱导 RAP80 易位至与 γ-H2AX 共定位的 DNA 损伤灶。我们进一步表明，这种易位还依赖于 RAP80 的 UIM，并且 UV 诱导的 RAP80 Ser205 磷酸化是由 ATR 介导的，而不是 ATM。我们的研究结果表明 RAP80 在不同类型的 DNA 损伤反应信号通路中具有更普遍的作用。

项目成果

RORγ directly regulates the circadian expression of clock genes and downstream targets in vivo.

• DOI: 10.1093/nar/gks630
• 发表时间: 2012-09-01
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Takeda Y;Jothi R;Birault V;Jetten AM
• 通讯作者: Jetten AM

CD44 plays a critical role in regulating diet-induced adipose inflammation, hepatic steatosis, and insulin resistance.

• DOI: 10.1371/journal.pone.0058417
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Kang HS;Liao G;DeGraff LM;Gerrish K;Bortner CD;Garantziotis S;Jetten AM
• 通讯作者: Jetten AM

Tsp57: a novel gene induced during a specific stage of spermatogenesis.

Tsp57：在精子发生的特定阶段诱导的新基因。

• DOI: 10.1095/biolreprod.103.018465
• 发表时间: 2004
• 期刊: Biology of reproduction
• 影响因子: 3.6
• 作者: Kim,Yong-Sik;Nakanishi,Gen;Oudes,AsaJ;Kim,KwanHee;Wang,Hang;Kilpatrick,DanielL;Jetten,AntonM
• 通讯作者: Jetten,AntonM

Retinoic acid-related orphan receptor γ directly regulates neuronal PAS domain protein 2 transcription in vivo.

• DOI: 10.1093/nar/gkq1335
• 发表时间: 2011-06
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Takeda Y;Kang HS;Angers M;Jetten AM
• 通讯作者: Jetten AM

Ubiquitin-interaction motifs of RAP80 are critical in its regulation of estrogen receptor alpha.

• DOI: 10.1093/nar/gkl1112
• 发表时间: 2007
• 期刊: NUCLEIC ACIDS RESEARCH
• 影响因子: 14.9
• 作者: Yan, Jun;Kim, Yong-Sik;Yang, Xiao-Ping;Albers, Michael;Koegl, Manfred;Jetten, Anton M.
• 通讯作者: Jetten, Anton M.