Abstract
The retinoblastoma (Rb) tumor suppressor gene product, pRb, has an established role in the implementation of cellular senescence, the state of irreversible G1 cell cycle arrest provoked by diverse oncogenic stresses. In murine cells, senescence cell cycle arrest can be reversed by subsequent inactivation of pRb, indicating that pRb is required not only for the onset of cellular senescence, but also for the maintenance of senescence program in murine cells. However, in human cells, once pRb is fully activated by p16INK4a, senescence cell cycle arrest becomes irreversible and is no longer revoked by subsequent inactivation of pRb, suggesting that p16INK4a/Rb-pathway activates an alternative mechanism to irreversibly block the cell cycle in human senescent cells. Here, we discuss the molecular mechanism underlying the irreversibility of senescence cell cycle arrest and its potential towards tumor suppression.
Highlights
Cellular senescence is the state of stable cell cycle arrest provoked by a variety of potentially oncogenic stimuli, such as telomere shortening, DNA damage or activation of certain oncogenes [1,2,3]
The activities of pRb and p53 are dramatically increased during cellular senescence and inactivation of these proteins in senescent mouse embryonic fibroblasts (MEFs) results in the reversal of the senescence phenotype leading to cell cycle re-entry, suggesting that pRb and p53 are required for the initiation of senescence program and for the maintenance of the senescence state in murine cells [1,2,3,11,12]
Using SVts8 cells, we were able to examine the irreversibility of senescence cell cycle arrest under various different conditions and have shown that p16INK4a/Rb-pathway cooperate with mitogenic signals to enforce irreversible cytokinetic block through activating production of reactive oxygen species (ROS) [16]
Summary
Cellular senescence is the state of stable cell cycle arrest provoked by a variety of potentially oncogenic stimuli, such as telomere shortening, DNA damage or activation of certain oncogenes [1,2,3]. Recent work in our lab has uncovered an unexpected role for the p16INK4a/Rb-pathway and provided a new insight into how senescent cell cycle arrest is enforced in human cells [16] In this commentary, we will take a closer look at the genes and mechanism involved. A dramatic increase of polynucleated cells is observed when pRb and p53 were subsequently inactivated in human cells expressing high level of p16INK4a [16], suggesting that this mechanism may target cytokinesis. Using SVts cells, we were able to examine the irreversibility of senescence cell cycle arrest under various different conditions and have shown that p16INK4a/Rb-pathway cooperate with mitogenic signals to enforce irreversible cytokinetic block through activating production of reactive oxygen species (ROS) [16]. This difference may account for the reversibility of murine cell senescence
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