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.
