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

Nucleic Acids Res. 2009 Aug;37(14):4657-71. doi: 10.1093/nar/gkp469. Epub 2009 Jun 5.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Animals
  • Cell Nucleus / chemistry
  • 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
  • RNA, Messenger / chemistry
  • Repressor Proteins / analysis
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Transcription Initiation Site

Substances

  • Jundp2 protein, mouse
  • Protein Isoforms
  • RNA, Messenger
  • Repressor Proteins