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Deletion of eIF2beta suppresses testicular cancer incidence and causes recessive lethality in agouti-yellow mice.

The agouti-yellow (A(y)) deletion is the only genetic modifier known to suppress testicular germ cell tumor (TGCT) susceptibility in mice or humans. The A(y) mutation deletes Raly and Eif2s2, and induces the ectopic expression of agouti, all of which are potential TGCT-modifying mutations. Here we report that the reduced TGCT incidence of heterozygous A(y) males and the recessive embryonic lethality of A(y) are caused by the deletion of Eif2s2, the beta subunit of translation initiation factor eIF2. We found that the incidence of affected males was reduced 2-fold in mice that were partially deficient for Eif2s2 and that embryonic lethality occurred near the time of implantation in mice that were fully deficient for Eif2s2. In contrast, neither reduced expression of Raly in gene-trap mice nor ectopic expression of agouti in transgenic or viable-yellow (A(vy)) mutants affected TGCT incidence or embryonic viability. In addition, we provide evidence that partial deficiency of Eif2s2 attenuated germ cell proliferation and differentiation, both of which are important to TGCT formation. These results show that germ cell development and TGCT pathogenesis are sensitive to the availability of the eIF2 translation initiation complex and to changes in the rate of translation.

Pubmed ID: 19168544

Authors

  • Heaney JD
  • Michelson MV
  • Youngren KK
  • Lam MY
  • Nadeau JH

Journal

Human molecular genetics

Publication Data

April 15, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: CA119623
  • Agency: NCI NIH HHS, Id: CA75056
  • Agency: NCI NIH HHS, Id: F32 CA119623
  • Agency: NCI NIH HHS, Id: F32 CA119623-01
  • Agency: NCI NIH HHS, Id: F32 CA119623-02
  • Agency: NCI NIH HHS, Id: F32 CA119623-02S1
  • Agency: NCI NIH HHS, Id: R01 CA075056
  • Agency: NCI NIH HHS, Id: R01 CA075056-07
  • Agency: NCI NIH HHS, Id: R01 CA075056-08
  • Agency: NCI NIH HHS, Id: R01 CA075056-09

Mesh Terms

  • Animals
  • Eukaryotic Initiation Factor-2
  • Gene Deletion
  • Genes, Lethal
  • Homozygote
  • Male
  • Mice
  • Mice, Transgenic
  • Testicular Neoplasms
  • Testis