Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis

摘要: Activating Ras mutations can induce either proliferation or senescence depending on the cellular context. To determine whether activation has context-dependent effects in mammary gland, we generated doxycycline-inducible transgenic mice that permit to be titrated. Low levels of - similar those found non-transformed mouse tissues expressing endogenous oncogenic Kras2 stimulate and epithelial hyperplasias. In contrast, high tumours bearing is Ink4a-Arf- dependent irreversible following downregulation. Chronic low-level induction results tumour formation, but only after spontaneous upregulation activated evasion checkpoints. Thus, high-level, not low-level, activates suppressor pathways triggers an senescent growth arrest vivo. We suggest a three-stage model for Ras-induced tumorigenesis consisting initial activating mutation, overexpression allele and, finally, p53-Ink4a-Arf-dependent