Studies on the irreversibility of cellular senescence and its role in vivo

点击翻译按钮获取中文摘要

Cellular senescence is a state of permanent cell cycle arrest that can be induced by a variety of potentially oncogenic stresses. It is therefore proposed as a fail-safe mechanism that protects normal cells from losing control of cell division and forming tumors. Although molecular mechanism inducing cellular senescence has been well studied in tissue culture cells, very little is known about how senescent cell cycle arrest is stably maintained in vivo. To gain further insight into the roles and mechanisms of cellular senescence in vivo, we attempted to elucidate molecular mechanisms underlying irreversibility of senescent cell cycle arrest. Towards this end, we utilized a conditionally immortalized cell line that express temperature-sensitive SV4- large T antigen. Using this cell line, we uncovered that p 16^<INK4a> tumor suppressor blocks not only DNA replication but also cytokinesis through activating reactive oxygen species (ROS) -PKCδsignalling in senescent human cells. Importantly, once activated by ROS, PKCδ promotes further generation of ROS, thus establishing a positive feedback loop to sustain ROS-PKCδsignalling. Sustained activation of ROS-PKCδ signalling irreversibly blocks cytokinesis, at least partly through blocking the function of LATS1/WARTS, a mitotic exit network kinase required for cytokinesis. We also established the transgenic mice lines expressing the firefly luciferase under the control of the senescence-associated gene promoter. In conjunction with a noninvasive bioluminescence imaging technique, these transgenic mice lines enabled us to monitor the senescence-associated gene expression in vivo. Using this system, we were able to unveil the dynamics of senescence signaling throughout entire lifespan in vivo. We hope that these studies will provide new insights into the development of cancer and open up new possibilities for its control.