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

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Activation of alternative Jdp2 promoters and functional protein isoforms in T-cell lymphomas by retroviral insertion mutagenesis. / Rasmussen, Mads Heilskov; Wang, Bruce; Wabl, Matthias; Nielsen, Anders Lade; Pedersen, Finn Skou.

I: Nucleic Acids Research, Bind 37, Nr. 14, 2009, s. 4657-71.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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@article{13ac5fe00c1311dfb95d000ea68e967b,
title = "Activation of alternative Jdp2 promoters and functional protein isoforms in T-cell lymphomas by retroviral insertion mutagenesis",
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.",
keywords = "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",
author = "Rasmussen, {Mads Heilskov} and Bruce Wang and Matthias Wabl and Nielsen, {Anders Lade} and Pedersen, {Finn Skou}",
year = "2009",
doi = "10.1093/nar/gkp469",
language = "English",
volume = "37",
pages = "4657--71",
journal = "Nucleic Acids Research",
issn = "0305-1048",
publisher = "Oxford University Press",
number = "14",

}

RIS

TY - JOUR

T1 - Activation of alternative Jdp2 promoters and functional protein isoforms in T-cell lymphomas by retroviral insertion mutagenesis

AU - Rasmussen, Mads Heilskov

AU - Wang, Bruce

AU - Wabl, Matthias

AU - Nielsen, Anders Lade

AU - Pedersen, Finn Skou

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

KW - Alternative Splicing

KW - Animals

KW - Cell Nucleus

KW - Genes, ras

KW - Introns

KW - Leukemia Virus, Murine

KW - Lymphoma, T-Cell

KW - Mice

KW - Mice, Inbred BALB C

KW - Mutagenesis, Insertional

KW - NIH 3T3 Cells

KW - Promoter Regions, Genetic

KW - Protein Isoforms

KW - RNA, Messenger

KW - Repressor Proteins

KW - Transcription Initiation Site

U2 - 10.1093/nar/gkp469

DO - 10.1093/nar/gkp469

M3 - Journal article

C2 - 19502497

VL - 37

SP - 4657

EP - 4671

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

IS - 14

ER -