NUDR--A Potential Tumor Suppressor of Childhood Cancers

Summary

Principal Investigator: Jodi I Huggenvik
Abstract: 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.
Funding Period: 2001-07-01 - 2007-06-30
more information: NIH RePORT

Top Publications

  1. pmc Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems
    Anneke T Vulto-van Silfhout
    Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
    Am J Hum Genet 94:649-61. 2014
  2. pmc Deformed epidermal autoregulatory factor-1 (DEAF1) interacts with the Ku70 subunit of the DNA-dependent protein kinase complex
    Philip J Jensik
    Department of Physiology, Southern Illinois University School of Medicine, Carbondale, Illinois, United States of America
    PLoS ONE 7:e33404. 2012
  3. ncbi FAS expression inversely correlates with PTEN level in prostate cancer and a PI 3-kinase inhibitor synergizes with FAS siRNA to induce apoptosis
    Sucharita Bandyopadhyay
    Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA
    Oncogene 24:5389-95. 2005
  4. ncbi Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression
    Sucharita Bandyopadhyay
    Southern Illinois University School of Medicine, Department of Medical Microbiology, Immunology and Cell Biology, 801 N Rutledge Street, PO Box 19626, Springfield, Illinois 62794 9626, USA
    Nat Med 12:933-8. 2006

Scientific Experts

  • Philip J Jensik
  • Sucharita Bandyopadhyay
  • Anneke T Vulto-van Silfhout
  • Jodi I Huggenvik
  • Michael W Collard
  • Sudha K Pai
  • Sadahiro Hosobe
  • Mary E Pauza
  • Ken Saito
  • Taisei Tsukada
  • Kunio Miura
  • Misako Watabe
  • Kounosuke Watabe
  • Shigeru Hirota
  • Megumi Iiizumi
  • Ying Wang
  • Nina De Rocker
  • Joseph Bulinski
  • Stacy L Ownby
  • Shivakumar Rajamanickam
  • Bregje W M van Bon
  • Hans van Bokhoven
  • Andy Willaert
  • Bjorn Menten
  • Joep de Ligt
  • Xiang Cai
  • Ramya Raghavan
  • Kelsey Jarrett
  • Kathryn J Newhall
  • Dorien Lugtenberg
  • Anita Rauch
  • Joris A Veltman
  • Bert B A de Vries
  • Gemma L Carvill
  • Gregory M Rose
  • G Stanley McKnight
  • Evan E Eichler
  • Han G Brunner
  • Christiane Zweier
  • Arjan P M de Brouwer
  • Alexander Hoischen
  • Heather C Mefford
  • Sarah Vergult
  • Sara N Reardon
  • Lisenka E L M Vissers
  • Sabine Endele
  • Petra F de Vries
  • Tara McIntyre
  • Sunao Hayashi
  • Asok Chaudhuri
  • Yukio Takano
  • Tomoyuki Mashimo
  • Sonia Mohinta
  • Eiji Furuta
  • Rui Zhan
  • Jodi Huggenvik
  • Stephen J Markwell
  • Steven C Gross

Detail Information

Publications4

  1. pmc Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems
    Anneke T Vulto-van Silfhout
    Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
    Am J Hum Genet 94:649-61. 2014
    ..Our results demonstrate that mutations in DEAF1 cause ID and behavioral problems, most likely as a result of impaired transcriptional regulation by DEAF1. ..
  2. pmc Deformed epidermal autoregulatory factor-1 (DEAF1) interacts with the Ku70 subunit of the DNA-dependent protein kinase complex
    Philip J Jensik
    Department of Physiology, Southern Illinois University School of Medicine, Carbondale, Illinois, United States of America
    PLoS ONE 7:e33404. 2012
    ....
  3. ncbi FAS expression inversely correlates with PTEN level in prostate cancer and a PI 3-kinase inhibitor synergizes with FAS siRNA to induce apoptosis
    Sucharita Bandyopadhyay
    Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA
    Oncogene 24:5389-95. 2005
    ..These results provide a strong rationale for exploring the therapeutic use of an inhibitor of the PTEN signaling pathway in conjunction with the FAS siRNA to inhibit prostate tumor growth...
  4. ncbi Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression
    Sucharita Bandyopadhyay
    Southern Illinois University School of Medicine, Department of Medical Microbiology, Immunology and Cell Biology, 801 N Rutledge Street, PO Box 19626, Springfield, Illinois 62794 9626, USA
    Nat Med 12:933-8. 2006
    ..These results provide direct evidence that DARC is essential for the function of CD82 as a suppressor of metastasis...