Monoallelic Loss of the Imprinted Gene Grb10 Promotes Tumor Formation in Irradiated Nf1+/- Mice

摘要: Imprinted genes are expressed from only one parental allele and heterozygous loss involving the is sufficient to produce complete of protein expression. Genetic alterations common in tumorigenesis but role imprinted this process not well understood. In earlier work we mutagenized mice for Neurofibromatosis I tumor suppressor gene (NF1) model radiotherapy-associated second malignant neoplasms that arise irradiated NF1 patients. Expression analysis cell lines established our mouse models identified Grb10 expression as widely absent. an polymorphism primary tumors demonstrates commonly lost diverse Nf1 mutant arising models. We performed functional studies test whether restoration or alter fundamental features growth. Restoring decreases proliferation, soft agar colony formation downregulates Ras signaling. Conversely, silencing untransformed embryo fibroblasts significantly increased proliferation Ras-GTP levels. a constitutively activated MEK rescued cells Grb10-mediated reduction formation. These reveal can occur during vivo tumorigenesis, with consequence cells. tumors, independently promotes pathway hyperactivation, which hyperproliferation, early feature development. context robust cancer identifies novel tumorigenesis.