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Human Molecular Genetics Advance Access originally published online on January 23, 2009
Human Molecular Genetics 2009 18(8):1395-1404; doi:10.1093/hmg/ddp045
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Jason D. Heaney*, Megan V. Michelson, Kirsten K. Youngren, Man-Yee J. Lam and Joseph H. Nadeau

Department of Genetics, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, OH 44120, USA

* To whom correspondence should be addressed. Tel: +1 2163680626; Fax: +1 2163683432; Email: jason.heaney{at}case.edu

Received December 30, 2008; Revised January 21, 2009; Accepted January 21, 2009

The agouti-yellow (Ay) deletion is the only genetic modifier known to suppress testicular germ cell tumor (TGCT) susceptibility in mice or humans. The Ay 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 Ay males and the recessive embryonic lethality of Ay 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 (Avy) 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.


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J. H. Nadeau
Transgenerational genetic effects on phenotypic variation and disease risk
Hum. Mol. Genet., October 15, 2009; 18(R2): R202 - R210.
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