The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells.
Cyclin E is often overexpressed in cancer tissue, leading to genetic instability and aneuploidy. Cullin 3 (Cul3) is a component of the BTB-Cul3-Rbx1 (BCR) ubiquitin ligase that is involved in the turnover of cyclin E. Here we show that liver-specific ablation of Cul3 in mice results in the persistence and massive expansion of hepatic progenitor cells. Upon induction of differentiation, Cul3-deficient progenitor cells underwent substantial DNA damage in vivo and in vitro, thereby triggering the activation of a cellular senescence response that selectively blocked the expansion of the differentiated offspring. Positive selection of undifferentiated progenitor cells required the expression of the tumor suppressor protein p53. Simultaneous loss of Cul3 and p53 in hepatic progenitors turned these cells into highly malignant tumor-initiating cells that formed largely undifferentiated tumors in nude mice. In addition, loss of Cul3 and p53 led to the formation of primary hepatocellular carcinomas. Importantly, loss of Cul3 expression was also detected in a large series of human liver cancers and correlated directly with tumor de-differentiation. The expression of Cul3 during hepatic differentiation therefore safeguards against the formation of progenitor cells that carry a great potential for transformation into tumor-initiating cells.
Institute for Molecular Biology, Hannover Medical School, Hannover, Germany.
Uta
U
Kossatz
Kai
K
Breuhahn
Benita
B
Wolf
Matthias
M
Hardtke-Wolenski
Ludwig
L
Wilkens
Doris
D
Steinemann
Stephan
S
Singer
Felicitas
F
Brass
Stefan
S
Kubicka
Brigitte
B
Schlegelberger
Peter
P
Schirmacher
Michael P
MP
Manns
Jeffrey D
JD
Singer
Nisar P
NP
Malek
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence / Q000502:physiology; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D019927:Cyclin E / Q000378:metabolism*; D004249:DNA Damage; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D006801:Humans; D008099:Liver / Q000166:cytology / Q000473:pathology / Q000502:physiology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C503646:Cul3 protein, mouse; D044842:Cullin Proteins; D019927:Cyclin E; D016159:Tumor Suppressor Protein p53