NUDR--A Potential Tumor Suppressor of Childhood Cancers

NUDR--儿童癌症的潜在肿瘤抑制剂

• 批准号: 6514855
• 负责人: Jodi Huggenvik
• 金额: $ 23.41万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY CARBONDALE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514855
• 关键词: 3T3 cells; RNA splicing; athymic mouse; cell cycle; gene mutation; gene targeting; genetically modified animals; heterogeneous nuclear ribonucleoprotein; insulinlike growth factor; polymerase chain reaction; protein structure function; recombinant proteins; southern blotting; transcription factor; tumor suppressor proteins; western blottings

NUDR is a mammalian transcription factor with homology to Drosophila DEAF-1, a developmental cofactor of Hox and homeodomain proteins. NUDR will regulate target genes in adults and during fetal development, and may influence the process of genomic imprinting. NUDR behaves as a transcriptional repressor by binding to CpG containing motifs found in target genes that include its own promoter and hnRNP A2/B1, an early biomarker of lung cancer. NUDR has sequence or structural homology to known and putative oncoproteins (c-myc, AML1/MTG8, SP100). NUDR is cell-cycle regulated and may recruit the corepressor N-CoR to produce chromatin remodeling. Mutations in NUDR cDNAs from tumor tissues have been identified that will produce truncated and altered proteins. Human ovarian and breast tumors show variable expression of a NUDR anti-sense gene, Nopps, which is encoded on the opposite strand as NUDR and may affect the expression of NUDR. Mutations in NUDR result in transformed cell phenotypes that produce tumors in athymic nude mice, thus mutated NUDR acts as an oncogene. Normal NUDR and Nopps produce strong tumor suppression of the childhood cancer cell line, RD. NUDR maps to the precise chromosomal region (11 p15.5) harboring multiple tumor suppressors for lung, liver, Wilms', and possibly many other cancers. Loss of imprinting at 11 p15.5 is likely to be an underlying mechanism for a number of pediatric and adult cancers, and based upon its profile, NUDR is the most likely candidate for the WT2 tumor suppressor. To investigate the normal physiological role of NUDR and Nopps, and to determine the role that NUDR functional domains may contribute to childhood cancers, we propose the following: 1) Establish stable cell lines expressing Nopps or NUDR functional domains. 2) Determine if the functional domains promote or inhibit tumor formation. 3) Eliminate the NUDR gene by homologous recombination in mouse and determine the physiological phenotypes. and 4) Determine if the Nopps tumor suppressor is expressed in mice and assess the feasibility for gene targeting. These studies will provide an understanding of how NUDR and Nopps act as tumor suppressors, how mutations in NUDR contribute to the development of childhood malignancies and adult cancers, and how global changes in chromosome function may affect oncogenic processes.

NUDR是哺乳动物转录因子，与果蝇（Dosophila Deaf-1）具有同源性（HOX和同源域蛋白的发育辅助因子）。 NUDR将调节成人和胎儿发育过程中的靶基因，并可能影响基因组印记的过程。 NUDR通过与含有靶基因的CPG结合，包括其自身启动子和HNRNP A2/B1（肺癌的早期生物标志物）中的CPG来表现为转录阻遏物。 NUDR与已知和推定的癌蛋白（C-MYC，AML1/MTG8，SP100）具有序列或结构同源性。 NUDR是受细胞周期调节的，可能会募集Corepressor n-Cor以产生染色质重塑。已经鉴定出将产生截短和改变的蛋白质的NUDR cDNA突变。人卵巢和乳腺肿瘤显示出NUDR抗敏感基因NOPP的可变表达，该基因NOPPs在相反的链上编码为NUDR，并可能影响NUDR的表达。 NUDR中的突变导致在无胸腺裸鼠中产生肿瘤的转化细胞表型，因此变异的NUDR充当癌基因。正常的NUDR和NOPP会对儿童癌细胞系产生强烈的肿瘤抑制。 NUDR地图到精确的染色体区域（11 p15.5），该区域含有多个肿瘤，肝脏，威尔姆斯和可能其他许多癌症的肿瘤抑制剂。在11 p15.5处失去印迹可能是许多儿科和成人癌症的基本机制，并且基于其概况，NUDR是WT2肿瘤抑制器的最可能候选者。为了研究NUDR和NOPP的正常生理作用，并确定NUDR功能域可能有助于儿童期癌症的作用，我们提出以下方面：1）建立表达NOPPS或NUDR功能域的稳定细胞系。 2）确定功能域是促进或抑制肿瘤的形成。 3）通过小鼠同源重组消除NUDR基因，并确定生理表型。 4）确定NOPPS肿瘤是否在小鼠中表达并评估基因靶向的可行性。这些研究将对NUDR和NOPP的充当肿瘤抑制剂，NUDR中的突变如何促进儿童恶性肿瘤和成人癌症的发展以及染色体功能的全球变化可能影响致癌过程。