Cyclin D as a Retinoid Molecular Target

Cyclin D 作为类视黄醇分子靶标

• 批准号: 7414124
• 负责人: ETHAN DMITROVSKY
• 金额: $ 29.94万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7414124
• 关键词: Address; Biological; Cell Cycle Arrest; Cell Line; Cells; Cisplatin; Clinical; Combined Modality Therapy; Cyclin D1; Cyclins; Degradation Pathway; Depth; Development; Differentiation and Growth; Direct Costs; Embryonal Carcinoma; Epidermal Growth Factor Receptor; Funding; Future; G1 Arrest; Germ cell tumor; Human; In Vitro; Kinetics; Knock-out; Learning; Link; Malignant Neoplasms; Mature Teratoma; Mediating; Modeling; Molecular; Molecular Profiling; Molecular Target; Neuronal Differentiation; Neurons; Nuclear Receptors; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Play; Proteins; Proteolysis; Published Comment; Publishing; Regulation; Relative (related person); Repression; Resistance; Resources; Retinoic Acid Receptor; Retinoids; Risk; Role; Signal Pathway; Solid Neoplasm; Staging; Teratoma; Text; Therapeutic; Threonine; Tissue Banks; Transfection; Translating; Tretinoin; Tumor Bank; Tumor Biology; Tumorigenicity; Ubiquitination; United States National Institutes of Health; Vitamin A; Work; chemotherapy; clinically relevant; cyclin D2; gene repression; human embryonal carcinoma cell; in vivo; insight; interest; male; neoplastic; neoplastic cell; novel; programs; promoter; response; therapeutic target; tumor; tumor growth; tumorigenic

DESCRIPTION (provided by applicant): This revised new NIH R01 application evaluates cyclin D1 as a molecular target for germ cell tumor (GCT) growth, maturation, and chemotherapy response. All-trans-retinoic acid (RA) induced a neuronal and non-tumorigenic state in the human GCT cell line, NT2/D1. We uncovered retinoic acid receptor (RARgamma) as regulating RA growth and differentiation in NT2/D1 cells and conferring RA resistance to NT2/D1-R1 cells. GCTs are useful to study tumor differentiation mechanisms. A unique clinical feature of GCTs is teratoma formation, reflecting their capacity to mature. An inverse relationship exists in GCTs between differentiation and tumorigenicity. To explore anti-neoplastic mechanisms in GCTs, NT2/D1 and NT2/D1-R1 cells were studied. NT2/D1 differentiation reproduced key features of teratomas in that RA-treatment caused these cells to mature and reduce tumorigenicity. A hallmark of this response is G1 arrest, at least partly through a previously unrecognized pathway, where retinoids trigger cyclin D1 proteolysis. This occurs partly through proteasomal degradation. RA effects on cyclin D1 are specific since cyclins D2 and D3 were not repressed. NT2/D1-R1 cells deregulated cyclin D1 expression. RARgamma transfection restored retinoid response and cyclin D1 repression to NT2/D1-R1 cells. Threonine 286 regulated cyclin D1 ubiquitination and proteasomal degradation by RA. Another relationship was that NT2/D1-R1 cells deregulated cyclin D1 and acquired cisplatin resistance, indicating a link between maturation and chemotherapy responses. Post-transcriptional and transcriptional retinoid mechanisms repressed cyclin D1. These will be studied comprehensively and compared to those of other cyclin D1 targeting agents. This is relevant for combination therapy. There is a need to uncover the cyclin D1 role in GCT biology these specific aims that: (1) elucidate proteolytic and transcriptional mechanisms that repress cyclin D1 during retinoid treatment of GCTs and learn whether other cyclin D1 targeting agents engage distinct or overlapping mechanisms; (2) validate whether cyclin D1 repression is required for GCT growth, maturation, or cisplatin response; and (3) extend findings to the clinical context by evaluating cyclin D1 as a target in a unique tissue bank with mature, immature, and chemotherapy resistant GCTs. These resources with pharmacologic, cell and molecular biological approaches would provide insights into cyclin D1 as a novel target for poor risk GCTs.

描述（由申请人提供）：该修订后的新NIH R 01申请评估了细胞周期蛋白D1作为生殖细胞肿瘤（GCT）生长、成熟和化疗反应的分子靶点。全反式维甲酸（RA）诱导人GCT细胞系NT 2/D1的神经元和非致瘤性状态。我们发现维甲酸受体（RAR γ）调节RA生长和分化的NT 2/D1细胞和赋予RA抗性NT 2/D1-R1细胞。GCT可用于研究肿瘤分化机制。GCT的一个独特的临床特征是畸胎瘤形成，反映了它们的成熟能力。GCT的分化程度与致瘤性呈负相关。为了探讨GCT的抗肿瘤机制，对NT 2/D1和NT 2/D1-R1细胞进行了研究。NT 2/D1分化再现了畸胎瘤的关键特征，因为RA处理导致这些细胞成熟并降低致瘤性。这种反应的一个标志是G1期阻滞，至少部分是通过以前未被认识的途径，其中维甲酸触发细胞周期蛋白D1蛋白水解。这部分通过蛋白酶体降解发生。RA对细胞周期蛋白D1的影响是特异性的，因为细胞周期蛋白D2和D3没有被抑制。NT 2/D1-R1细胞周期蛋白D1表达下调。RAR γ转染恢复了对NT 2/D1-R1细胞的类维生素A反应和细胞周期蛋白D1抑制。Threaten 286调节RA引起的细胞周期蛋白D1泛素化和蛋白酶体降解。另一个关系是NT 2/D1-R1细胞去调节细胞周期蛋白D1和获得顺铂耐药性，表明成熟和化疗反应之间的联系。转录后和转录类维生素A机制抑制细胞周期蛋白D1。这些将被全面研究，并与其他细胞周期蛋白D1靶向药物进行比较。这与联合治疗相关。需要揭示细胞周期蛋白D1在GCT生物学中的作用，这些特定的目的是：（1）阐明在类维生素A治疗GCT期间抑制细胞周期蛋白D1的蛋白水解和转录机制，并了解其他细胞周期蛋白D1靶向剂是否参与不同或重叠的机制;（2）验证细胞周期蛋白D1抑制是否是GCT生长、成熟或顺铂反应所需的;和（3）通过在具有成熟、未成熟和化疗抗性GCT的独特组织库中评估作为靶点的细胞周期蛋白D1，将发现扩展到临床背景。这些资源与药理学，细胞和分子生物学方法将提供深入了解细胞周期蛋白D1作为一个新的目标，为穷人的风险GCT。