Sarkisian Christopher J, Keister Blaine A, Stairs Douglas B, Boxer Robert B, Moody Susan E, Chodosh Lewis A
Department of Cancer Biology, The Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160, USA.
Nat Cell Biol. 2007 May;9(5):493-505. doi: 10.1038/ncb1567. Epub 2007 Apr 22.
Activating Ras mutations can induce either proliferation or senescence depending on the cellular context. To determine whether Ras activation has context-dependent effects in the mammary gland, we generated doxycycline-inducible transgenic mice that permit Ras activation to be titrated. Low levels of Ras activation - similar to those found in non-transformed mouse tissues expressing endogenous oncogenic Kras2 - stimulate cellular proliferation and mammary epithelial hyperplasias. In contrast, high levels of Ras activation - similar to those found in tumours bearing endogenous Kras2 mutations - induce cellular senescence that is Ink4a-Arf- dependent and irreversible following Ras downregulation. Chronic low-level Ras induction results in tumour formation, but only after the spontaneous upregulation of activated Ras and evasion of senescence checkpoints. Thus, high-level, but not low-level, Ras activation activates tumour suppressor pathways and triggers an irreversible senescent growth arrest in vivo. We suggest a three-stage model for Ras-induced tumorigenesis consisting of an initial activating Ras mutation, overexpression of the activated Ras allele and, finally, evasion of p53-Ink4a-Arf-dependent senescence checkpoints.
激活型Ras突变可根据细胞环境诱导增殖或衰老。为了确定Ras激活在乳腺中是否具有环境依赖性作用，我们构建了强力霉素诱导型转基因小鼠，使Ras激活能够被滴定。低水平的Ras激活——类似于在表达内源性致癌Kras2的未转化小鼠组织中发现的水平——刺激细胞增殖和乳腺上皮增生。相比之下，高水平的Ras激活——类似于在携带内源性Kras2突变的肿瘤中发现的水平——诱导细胞衰老，这种衰老依赖Ink4a-Arf且在Ras下调后不可逆。慢性低水平Ras诱导会导致肿瘤形成，但只有在活化Ras自发上调并逃避衰老检查点之后才会发生。因此，高水平而非低水平的Ras激活会激活肿瘤抑制途径并在体内触发不可逆的衰老生长停滞。我们提出了一个Ras诱导肿瘤发生的三阶段模型，包括最初的激活型Ras突变、激活型Ras等位基因的过表达，以及最终逃避p53-Ink4a-Arf依赖性衰老检查点。
