Sci. Aging Knowl. Environ., 31 October 2001
They're Alive! Protein potion brings senescent cells back from the (un)dead
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/abstract/sageke;2001/5/nw18
Key Words: Mdm2 E2F p53 replicative senescence adenovirus fibroblast human
Abstract: Like zombies, senescent cells join the ranks of the undead. They no longer divide, but they don't die either. Now it turns out that these cellular freaks possess the resources for resurrection to a more vigorous existence: The right brew of normal proteins can kick-start DNA replication in the stalled cells.
Until now, scientists needed deviant proteins to shock senescent cells back to life: Cancer-causing molecules activate two cellular pathways that stimulate division. In the new work, Sarraj and colleagues mixed and matched benign proteins, looking for a combination that spurs senescent cells to start reproducing again. They tested Mdm2, which distracts the p53 protein from one of its usual jobs: inhibiting cell proliferation. Other candidates were three E2F proteins, which boost the production of molecules that encourage cells to multiply. Because senescent cells contain more p53 and less E2F than do normal cells, the researchers reasoned that providing additional Mdm2 or E2F might trigger cell duplication. To test this idea, they infected senescent human fibroblasts--cells that compose connective tissue--with various combinations of viruses, each of which is engineered to produce one of these proteins. By looking for incorporation of a tagged molecule into DNA, they were able to determine what fraction of cells copied their DNA--an indication that cell division had started up again. Serving up extra Mdm2 or E2F individually had a modest effect: 10% to 30% of the cells showed signs of replicative life. But Mdm2 plus any one of the three E2Fs jolted 50% to 70% of the cells back into action.
Scientists have suspected that the right blend of cellular proteins could recharge senescent cells, but they hadn't shown that experimentally until now. The results provide evidence that supplying certain proteins lacking in senescent cells can indeed reverse the process. The study enhances our knowledge about possible links between senescence and cancer or aging. In animals, senescence might fight cancer by stunting the growth of damaged cells before they start dividing unchecked (see "Dangerous Liaisons"). And accumulation of senescent cells might be to blame for some of the effects of aging (see "More Than a Sum of Our Cells"). But no one's likely to start receiving antiaging E2F/Mdm2 injections any time soon: The treated cells might retain the harmful characteristics that sparked senescence in the first place and rejuvenating them might just produce more of a bad thing. But knowing how to bring senescent cells back to life will undoubtedly shed light on the spell that makes them zombies in the first place.
--R. John Davenport; suggested by Chang-Su Lim
S. Sarraj, R. Farb, R. Martell, Reconstitution of DNA synthetic capacity in senescent normal human fibroblasts by expressing cellular factors E2F and Mdm2. Exp. Cell Res. 270, 268-276 (2001). [Abstract] [PDF]
Citation: R. J. Davenport, They're Alive! Protein potion brings senescent cells back from the (un)dead. Science's SAGE KE (31 October 2001), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2001/5/nw18
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