Genetic interaction between the unstable v-Ha-RAS transgene (Tg.AC) and the murine Werner syndrome gene: Transgene instability and tumorigenesis

Aya Leder, Michel Lebel, Fen Zhou, Karen Fontaine, Alexander J Bishop, Philip Leder

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Tg.AC transgenic mice provide a sensitive assay for oncogenic agents and a convenient alternative to the two-stage initiation/promoter model of skin tumorigenesis. Although extensively used, this model has remained in part an enigma since mice that carry the Tg.AC transgene (consisting of v-Ha-Ras driven by an embryonic ζ-globin promoter) would not ordinarily be expected to develop skin and other adult tumors. Cloning and characterizing the inserted transgene has provided an insight into the Tg.AC phenotype. We find that the transgene is inserted into a Line-1 element in such a way as to create extended inverted repeats consisting of both transgene and Line-1 sequences. Such structures would be expected to contribute to the instability of the Tg.AC locus and we suggest that this instability is critical to the Tg.AC phenotype. Further, we strengthen this notion by introducing an inactivating mutation in the murine Wrn gene (a gene important in maintenance of genome stability) and showing that bigenic Tg.AC/WrnΔhel/Δhel mice experience an eightfold increase in inactivating germline mutations at the Tg.AC locus. Similarly, Tg.AC/WrnΔhel/Δhel mice that retain an intact and thus active Tg.AC locus experience a sharp increase in papillomas as compared to Tg.AC/Wrn+/+ mice. This work demonstrates a genetic interaction between the instability of the multicopy transgene and the Werner Syndrome gene. From this, we conclude that genetic instability remains a key element in this tumor promoter model.

Original languageEnglish (US)
Pages (from-to)6657-6668
Number of pages12
JournalOncogene
Volume21
Issue number43
DOIs
StatePublished - Sep 26 2002
Externally publishedYes

Fingerprint

Werner Syndrome
Transgenes
Carcinogenesis
Genes
Phenotype
Skin
Globins
Germ-Line Mutation
Genomic Instability
Papilloma
Carcinogens
Transgenic Mice
Organism Cloning
Maintenance
Mutation
Neoplasms

Keywords

  • Genome instability
  • TPA
  • Transgenic mouse
  • v-Ha-RAS
  • Werner syndrome

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Genetic interaction between the unstable v-Ha-RAS transgene (Tg.AC) and the murine Werner syndrome gene : Transgene instability and tumorigenesis. / Leder, Aya; Lebel, Michel; Zhou, Fen; Fontaine, Karen; Bishop, Alexander J; Leder, Philip.

In: Oncogene, Vol. 21, No. 43, 26.09.2002, p. 6657-6668.

Research output: Contribution to journalArticle

Leder, Aya ; Lebel, Michel ; Zhou, Fen ; Fontaine, Karen ; Bishop, Alexander J ; Leder, Philip. / Genetic interaction between the unstable v-Ha-RAS transgene (Tg.AC) and the murine Werner syndrome gene : Transgene instability and tumorigenesis. In: Oncogene. 2002 ; Vol. 21, No. 43. pp. 6657-6668.
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