We have recently generated a conditional allele of Rb using the Cre/loxP system in order to model sporadic cancers associated with Rb mutations in humans.

Taking advantage of this conditional allele, we found that acute loss of Rb was sufficient to reverse quiescence and senescence in MEFs (see time-lapse movie in which senescent Rb conditional mutant MEFs have been infected with adeno-Cre and re-enter the cell cycle). This observation was unexpected because the senescence cell cycle arrest was thought to be “irreversible”, in order to prevent proliferation of aging and damaged cells.

This result raises the intriguing possibility that senescent or differentiated post-mitotic adult cells are not permanently arrested and may have the capacity to re-enter the cell cycle and to dedifferentiate into a “cancer progenitor” state. Therefore, the pool of potential target cells for cancer may not be limited to a small pool of mutant stem cells, and may be much larger than previously anticipated.

Furthermore, under the same conditions (quiescence and senescence), germline Rb-/- cells behaved similarly to wild-type cells, suggesting that developmental adaptation and functional compensation within the Rb family may render cells less sensitive to loss of Rb function (see link). These data show for the first time that acute mutation of a gene may have different phenotypic consequences than its germline deletion, which has important consequences in the mouse modeling field and in other genetic systems.