The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells

摘要: Cyclin E is often overexpressed in cancer tissue, leading to genetic instability and aneuploidy. Cullin 3 (Cul3) a component of the BTB-Cul3-Rbx1 (BCR) ubiquitin ligase that involved turnover cyclin E. Here we show liver-specific ablation Cul3 mice results persistence massive expansion hepatic progenitor cells. Upon induction differentiation, Cul3-deficient cells underwent substantial DNA damage vivo vitro, thereby triggering activation cellular senescence response selectively blocked differentiated offspring. Positive selection undifferentiated required expression tumor suppressor protein p53. Simultaneous loss p53 progenitors turned these into highly malignant tumor-initiating formed largely tumors nude mice. In addition, led formation primary hepatocellular carcinomas. Importantly, was also detected large series human liver cancers correlated directly with de-differentiation. The during differentiation therefore safeguards against carry great potential for transformation