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The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells
Uta Kossatz, … , Jeffrey D. Singer, Nisar P. Malek
Uta Kossatz, … , Jeffrey D. Singer, Nisar P. Malek
Published October 11, 2010
Citation Information: J Clin Invest. 2010;120(11):3820-3833. https://doi.org/10.1172/JCI41959.
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Research Article Oncology

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

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Abstract

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.

Authors

Uta Kossatz, Kai Breuhahn, Benita Wolf, Matthias Hardtke-Wolenski, Ludwig Wilkens, Doris Steinemann, Stephan Singer, Felicitas Brass, Stefan Kubicka, Brigitte Schlegelberger, Peter Schirmacher, Michael P. Manns, Jeffrey D. Singer, Nisar P. Malek

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Figure 5

Maintenance of senescence by p53 is essential for preventing the generation of tumor-initiating stem cells.

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Maintenance of senescence by p53 is essential for preventing the generat...
(A) Quantitation of p16 expression in the indicated liver cells from Cul3/p53 double-knockout animals at 10–11 weeks after birth. Values are shown as difference relative to p16-positive cells in livers from Cul3 single-knockout animals (compare Figure 2F) (n = 3/group). (B) Quantitation of γ-H2AX expression in the indicated liver cells from Cul3/p53 double knockout animals at 10–11 weeks after birth. Values are shown as difference relative to γ-H2AX–positive cells in livers from Cul3 single-knockout animals (compare Figure 2C) (n = 3/group). (C) Quantitation of γ-H2AX staining by immunofluorescence at the indicated time points after the induction of differentiation. Asynchronously growing cells were set as 100%. (D) Quantitation of S-phase cells by BrdU uptake at the indicated time points after the induction of differentiation. (E) Comparative genomic hybridization analysis of Cul3 and Cul3/p53 double-knockout cells after induction of differentiation for 96 hours compared with undifferentiated cells of the identical genotype. *P < 0.05, **P < 0.005.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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