Non-Proliferation as an Active State: Conceptual and Practical Implications

We have recently shown that all kinds of non-proliferating cells, including quiescent, senescent, and terminally differentiated ones, can be mitotically reactivated by the sole removal of cell type-specific cyclin-dependent kinase inhibitors. Reactivation takes place irrespective of added growth factors, allowing otherwise quiescent or senescent cells to proliferate. These unexpected findings warrant a reappraisal of some key aspects of the cell cycle. Inhibitors do not only modulate kinase activity, but contribute to the decision to enter the cell cycle as much as cyclins themselves. Non-proliferating cells, even those destined never to reenter the cell cycle, continue to express functionally significant levels of preassembled cyclin-cdk complexes, making cell cycle-arrest a state that must be constantly maintained by active expression of cyclin-dependent kinase inhibitors (CKIs). In addition, we suggest that the novel findings can be exploited in human therapy to accelerate, promote, or induce cell proliferation, both in vitro and in vivo. They should prove advantageous in cell biotechnology, cell replacement therapy, and tissue repair, wherever cell proliferation constitutes a limiting factor.