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. Roralpha和Gamma：与类维生素性相关的孤儿受体A和G（Rora和Rorg）是核受体超家族的成员。为了鉴定RORA和G的生理功能，分析了缺乏RORA和G功能的小鼠。 RORG在免疫系统中表现出多个功能。 RORG表达对于淋巴结器官发生是必不可少的，并且在胸腺细胞稳态中起关键作用。 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均被诱导，双敲除小鼠对实验性自身免疫性脑脊髓炎有抵抗力，这是多发性硬化症的模型。此外，RORG缺陷的小鼠不太容易受到大小（OVA）诱导的小鼠的炎症，这是一种过敏性气道疾病的模型。 类视黄素相关的孤儿受体α（Rora）和伽马（RORG）均在肝脏中表达。但是，它们在该组织中的生理功能尚未明确定义。 RORA1和RORG1在昼夜节律期间显示出表达的振荡模式。 WT，RORA缺陷型小鼠（Rorasg/sg），Rorg - / - 和Rorasg/Sgrorg - / - 双敲除（DKO）小鼠的基因表达谱的比较，通过微阵列分析表明，Rora和Rorg尤其重要，尤其重要，其中几个均具有数量的ENES，该阶段尤其重要。 3B-羟基固醇脱氢酶（HSD3B），细胞色素P450（CYP）酶和磺胺转移酶。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受体会影响几种代谢途径的调节，包括参与类固醇，胆汁酸和异种生物的代谢的途径，这表明ROR在控制代谢稳态方面很重要。 ii。 TAK1：核孤儿受体TAK1充当转录的阳性和负调节剂；但是，对介导其活动的因素知之甚少。使用TAK1的配体结合结构域作为诱饵鉴定出一种新型的Tak1相互作用蛋白，称为TIP27的酵母两杂化分析。我们的研究表明，TIP27是TAK1转录激活的有效阻遏物，因此可能在TAK1调节几种生理功能中起关键作用。 TAK1敲除小鼠的产生显示了目前正在研究的几种表型。 iii。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，以一种依赖性的方式与Esstrogen受体α（ERA）相互作用。此外，RAP80与DNA修复有关，与肿瘤抑制乳腺癌-1（BRCA1）蛋白复合物有关。这种相互作用是通过BRCA1的BRCT重复序列介导的。 RAP80转移到电离辐射诱导的灶（IRIF），并介导BRCA1转移到IRIFS。我们表明，这种易位取决于Rap80的UIM。我们证明，与乳腺癌风险增加有关的BRCA1，R1699W的BRCT突变体无法与RAP80相互作用。触发性 - 塞捷克性突变的蛋白激酶（ATM）可以在Ser205的体外磷酸化Rap80。使用抗Rap80ser205p抗体，该抗体专门识别在Ser205处磷酸化的Rap80抗体，我们证明Rap80Ser205p转移到IRIF。我们表明，这种磷酸化是由ATM介导的，不需要功能性BRCA1。磷酸化发生在辐照后5分钟内发生。紫外线（UV）辐射还诱导与γ-H2AX共定位的Rap80易位。我们进一步表明，这种易位还取决于Rap80的UIM，并且在Ser205上紫外线诱导的Rap80的磷酸化是由ATR介导的，而不是ATM。我们的发现表明，Rap80在不同类型的DNA损伤响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.