Activation of alternative Jdp2 promoters and functional protein isoforms in T-cell lymphomas by retroviral insertion mutagenesis

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  • Department of Human Genetics
  • Interdisciplinary Nanoscience Center
  • Department of Molecular Biology
Retroviral insertional mutagenesis has been instrumental for the identification of genes important in cancer development. The molecular mechanisms involved in retroviral-mediated activation of proto-oncogenes influence the distribution of insertions within specific regions during tumorigenesis and hence may point to novel gene structures. From a retroviral tagging screen on tumors of 1767 SL3-3 MLV-infected BALB/c mice, intron 2 of the AP-1 repressor Jdp2 locus was found frequently targeted by proviruses resulting in upregulation of non-canonical RNA subspecies. We identified several promoter regions within 1000 bp upstream of exon 3 that allowed for the production of Jdp2 protein isoforms lacking the histone acetylase inhibitory domain INHAT present in canonical Jdp2. The novel Jdp2 isoforms localized to the nucleus and over-expression in murine fibroblast cells induced cell death similar to canonic Jdp2. When expressed in the context of oncogenic NRAS both full length Jdp2 and the shorter isoforms increased anchorage-independent growth. Our results demonstrate a biological function of Jdp2 lacking the INHAT domain and suggest a post-genomic application for the use of retroviral tagging data in identifying new gene products with a potential role in tumorigenesis.
Original languageEnglish
JournalNucleic Acids Research
Volume37
Issue14
Pages (from-to)4657-71
Number of pages14
ISSN0305-1048
DOIs
Publication statusPublished - 2009

    Research areas

  • Alternative Splicing, Animals, Cell Nucleus, Genes, ras, Introns, Leukemia Virus, Murine, Lymphoma, T-Cell, Mice, Mice, Inbred BALB C, Mutagenesis, Insertional, NIH 3T3 Cells, Promoter Regions, Genetic, Protein Isoforms, RNA, Messenger, Repressor Proteins, Transcription Initiation Site

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