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 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.
Rasmussen
Mads Heilskov
MH
Department of Molecular Biology, Aarhus University, Arhus, DK 8000, Denmark.
Wang
Bruce
B
Wabl
Matthias
M
Nielsen
Anders Lade
AL
Pedersen
Finn Skou
FS
D017398:Alternative Splicing; D000818:Animals; D002467:Cell Nucleus / Q000737:chemistry; D011905:Genes, ras; D007438:Introns; D009052:Leukemia Virus, Murine / Q000235:genetics*; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016254:Mutagenesis, Insertional; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000737:chemistry; D012097:Repressor Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D024363:Transcription Initiation Site
C491386:Jundp2 protein, mouse; D020033:Protein Isoforms; D012333:RNA, Messenger; D012097:Repressor Proteins