GATA4 functions as a key switch in the senescence regulatory network to activate the SASP. The nonsenescent state is maintained by inhibitory barriers that prevent cell cycle arrest and inflammation. Upon senescence-inducing signals, ATM and ATR relieve inhibition of the p53 and p16INK4a pathways to induce growth arrest and also block p62-dependent autophagic degradation of GATA4, resulting in NF-κB activation and SASP induction.
A team of researchers from Harvard Medical School and Buck Institute for Research on Aging has conducted a study that has revealed that GATA4 (a transcription factor) plays a significant role in cell senescence.
Cell senescence is a state that cells enter as they age or react to damage or other problems—once in this state they no longer progress through the cell cycle. Under normal conditions, senescence is a way for the body to maintain a healthy state. Sometimes however, the process does not work quite right and cells in a senescence state can accumulate, and that is a problem because it can lead to inflammation, neurodegenerative diseases or cancer. In order to understand and prevent such buildups, scientists need to better understand senescence-associated secretory phenotype (SASP) which is where a rise in pro-inflammatory growth factors, cytokines and chemokines and proteases occurs. In this new effort, the researchers looked at GATA4, a transcription factor (a protein that controls the transcription of genetic information from DNA to RNA) that has been associated with senescence in the past, but whose role was not clear.
METHOD: The team caused senescence to come about in a sample of human connective tissue cells then scanned them closely to spot genetic elements that were expressed in large amounts by senescent cells but not in nonsenescent cells.
RESULTS: 1. They found that in normal cells, GATA4 was held back by autophagy—in cells that entered senescence, on the other hand, GATA4 was not held back as much. This suggested that GATA4 actually plays a key role in activating senescence.
2. It helped to solve the problem of whether autophagy is a requirement for senescence to come about or whether it actually inhibits it from occurring. The new results suggest that it is a selective process; non-targeted autophagy appears to be part of the initiation process whereas targeted autophagy of GATA4 actually stops it. They also saw that removing some autophagy components actually increased the number of GATA4 proteins. Additionally, they found that when GATA4 was expressed, genes linked with SASP were expressed, and when it was not, the same genes were not expressed.
http://www.sciencemag.org/content/349/6255/aaa5612
http://medicalxpress.com/news/2015-09-gata4-key-role-cell-senescence.html
Recent Comments