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Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry


Cancer cells arise from normal cells through the acquisition of a series of mutations in oncogenes and tumour suppressor genes1. Mouse models of human cancer often rely on germline alterations that activate or inactivate genes of interest. One limitation of this approach is that germline mutations might have effects other than somatic mutations, owing to developmental compensation2,3. To model sporadic cancers associated with inactivation of the retinoblastoma (RB) tumour suppressor gene in humans, we have produced a conditional allele of the mouse Rb gene. We show here that acute loss of Rb in primary quiescent cells is sufficient for cell cycle entry and has phenotypic consequences different from germline loss of Rb function. This difference is explained in part by functional compensation by the Rb-related gene p107. We also show that acute loss of Rb in senescent cells leads to reversal of the cellular senescence programme. Thus, the use of conditional knockout strategies might refine our understanding of gene function and help to model human cancer more accurately.

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Figure 1: Acute deletion of Rb in MEFs.
Figure 2: Effects of acute versus germline loss of Rb function in quiescent cells.
Figure 3: Reversal of senescence after acute loss of Rb.


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We thank R. Jaenisch, S. Lowe and B. Kennedy for various useful reagents; D. Tuveson for helpful discussions; A. Brunet, K. Johnson and M. McLaughlin for critical reading of the manuscript; and members of F. Gertler's laboratory for help with the videomicroscopy experiments. This work was supported by funding from the Human Frontier Science Program, the Medical Foundation and the Merck/MIT postdoctoral fellowship program (J.S.), and from the National Cancer Institute and the Howard Hughes Medical Institute (T.J.).

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Correspondence to Tyler Jacks.

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Sage, J., Miller, A., Pérez-Mancera, P. et al. Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature 424, 223–228 (2003).

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