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

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 h...

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Bibliographic Details
Published in:Nucleic acids research 2009-08, Vol.37 (14), p.4657-4671
Main Authors: Rasmussen, Mads Heilskov, Wang, Bruce, Wabl, Matthias, Nielsen, Anders Lade, Pedersen, Finn Skou
Format: Article
Language:English
Subjects:
Alternative Splicing
Animals
Cell Nucleus - chemistry
Gene Regulation, Chromatin and Epigenetics
Genes, ras
Introns
Leukemia Virus, Murine - genetics
Lymphoma, T-Cell - genetics
Lymphoma, T-Cell - metabolism
Mice
Mice, Inbred BALB C
Mutagenesis, Insertional
NIH 3T3 Cells
Promoter Regions, Genetic
Protein Isoforms - analysis
Protein Isoforms - genetics
Protein Isoforms - metabolism
Repressor Proteins - analysis
Repressor Proteins - genetics
Repressor Proteins - metabolism
RNA, Messenger - chemistry
Transcription Initiation Site
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Summary: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.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkp469