These myotubes have reentered the cell cycle after p21 removal.

It may be specialized, but a muscle cell is just a single step away from resuming division, as Pajalunga et al. reveal on page 807. The researchers show that removing one regulatory protein can push a range of nondividing cells back into the cell cycle.

Most cells in adults aren't cycling. Some have slipped into quiescence, a temporary lull triggered by scarcity of food or other necessities. Cells whose telomeres have worn down or that carry damaged DNA often retire by entering replicative senescence. And terminally differentiated cells are so specialized that they no longer divide. Although researchers can jump-start the cell cycle by, for example, adding growth factors, the recipe for reactivating cells in each state is different.

To their surprise, Pajalunga et al. found that a common factor, a protein called p21, controls whether all three types of cells reenter the cell cycle. p21 is a cyclin-dependent kinase inhibitor, or CKI, which counters division-triggering kinases.

Myotubes, or differentiated muscle cells, are stubborn, shrugging off growth factors, oncogenes, and other division promoters. But when the researchers used RNAi to quash p21, the cells awakened and underwent mitosis—though they usually died shortly afterward. “This is the first time anyone has reactivated terminally differentiated cells by removing something from them,” says team leader Marco Crescenzi. Eliminating p21 also restarted proliferation in quiescent and senescent cells, which continued to divide rather than dying.

The researchers wondered how the myotubes were able to respond without growth factors, which spur the assembly of the cyclin/cdk complexes essential for the cell cycle. Myotubes contain prefabricated complexes, the scientists determined, but p21 hooks onto and inactivates them. The results suggest that even differentiated cells are poised to reenter the cell cycle; they will start dividing if they don't get continuous inhibition from CKIs. The discovery could provide a boost to tissue engineering by allowing researchers to raise cells that are reluctant to grow in culture.