| |||
|
|
|||
|
      |
|
 |
|
| |||||||||||
| |||||||||||
| |||||||||||
| | | | ||||||||
| Cell senescence: Under arrest
A positive feedback loop between reactive oxygen species (ROS) and protein kinase Cδ (PKCδ) cooperates with the retinoblastoma tumor suppressor pathway to irreversibly arrest senescent cells. Keeping the cell cycle under control is essential for tissue homeostasis and the prevention of cancer development. Tumor suppressors such as retinoblastoma protein (pRb) and its activator p16INK4a induce cellular senescence — a terminal differentiation state in which cells are metabolically active but cease to divide indefinitely. In Nature Cell Biology, Eiji Hara and colleagues uncover a positive feedback loop between reactive oxygen species (ROS) and protein kinase Cδ (PKCδ) that irreversibly arrests the cell-cycle downstream of p16INK4a and pRb.
The authors activated both the pRb and p53 cell cycle arrest/senescence pathways by inactivating the temperature sensitive SV40 large T antigen. They found that high serum levels contributed to the induction of irreversible cell-cycle arrest, indicating that mitogenic signals cooperate with tumor suppressors in the induction of senescence. Mitogenic signaling increases ROS levels, which are known to be involved in the onset of senescence. Interestingly, Hara and colleagues show that neutralizing the high ROS levels found in senescent cells with oxygen radical scavengers promoted a re-initiation of proliferation. As ROS activate PKCδ to further the production of oxygen radicals, a positive feedback loop that sustains high levels of ROS is established. In addition, they show that PKCδ blocks cell division, at least in part, by inducing proteasomal degradation of WARTS (also known as LATS), a mitotic exit network kinase required for cytokinesis. ROS-PKCδ signaling was reduced upon prevention of cellular senescence by RNAi-mediated depletion of p16INK4a. Conversely, ROS-PKCδ signaling increased in senescent human diploid fibroblasts and upon RNAi-mediated depletion of DNA-binding protein-1 (DP1), an essential activator of the transcription factor E2F. Together, these findings indicate that the p16INK4a-pRb pathway causes cell-cycle arrest by blocking E2F activity, which not only prevents DNA replication but also activates ROS production by increasing the levels of manganese superoxide dismutase. This study sheds mechanistic insight into the effects of p16INK4a in aging, and more importantly, it paradoxically demonstrates a role for ROS as tumor suppressors, which may help to explain the conflicting results in the use of anti-oxidants in cancer prevention. Monica Hoyos Flight
References
| |
| ||||||||
| |||||||||||
 | |||||||||||
| |||||||||||
| |||||||||||
| |||||||||||
HOME | SIGNALING UPDATE | MOLECULE PAGES | DATA CENTER | ABOUT US | |||||||||||
| |||||||||||
