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

Julien Sage, Abigail L. Miller, Pedro A. Pérez-Mancera, Julianne M. Wysocki and Tyler Jacks ()
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Julien Sage: Massachusetts Institute of Technology
Abigail L. Miller: Massachusetts Institute of Technology
Pedro A. Pérez-Mancera: CSIC/Universidad de Salamanca
Julianne M. Wysocki: Massachusetts Institute of Technology
Tyler Jacks: Massachusetts Institute of Technology

Nature, 2003, vol. 424, issue 6945, 223-228

Abstract: Abstract 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.

Date: 2003
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DOI: 10.1038/nature01764

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