A Novel Mechanism of Irreversible Cell Cycle Arrest in Cellular Senescence

Cellular senescence is the state of permanent cell cycle arrest evoked by numerous oncogenic stimuli. Thus, cellular senescence appears to act as a barrier to cancer, preventing damaged cells from undergoing proliferation. pRb and p53 have been shown to play key roles in cellular senescence. The activities of pRb and p53 are dramatically increased during cellular senescence, and inactivation of these proteins allows early passage cells to proliferate beyond the proliferation limit. Moreover, it has recently been shown that subsequent inactivation of pRb and/or p53 in senescent mouse embryonic fibroblasts results in the reversal of the senescence phenotype and causes cell cycle re-entry. However, in human cells, once pRb is fully engaged, particularly by its activator, p16INK4a, senescent growth arrest becomes irreversible, and is no longer revoked by subsequent inactivation of pRb and p53. However, it is largely unknown how the p16INK4a/Rb pathway induces irreversible cell cycle arrest in human senescent cells. Recently, we uncovered a novel pathway, by which pRb irrevocably blocks cytokinesis in human senescent cells. This irrevocable cell cycle arrest, which seems to be specific to human cells, is likely to act as a second barrier to cellular immortalization and may help to explain the remarkable stability of senescent growth arrest in human cells.