Abstract
Mouse embryonic fibroblasts (MEFs) are commonly grown in cell culture and are known to enter senescence after a low number of passages as a result of oxidative stress. Oxidative stress has also been suggested to promote centrosome disruption; however, the contribution of this organelle to senescence is poorly understood. Therefore, this study aimed to assess the role of the centrosome in oxidative stress induced-senescence using MEFs as a model. We demonstrate here that coincident with the entry of late-passage MEFs into senescence, there was an increase in supernumerary centrosomes, most likely due to centrosome fragmentation. In addition, disrupting the centrosome in early-passage MEFs by depletion of neural precursor cell expressed developmentally downregulated gene 1 (NEDD1) also resulted in centrosomal fragmentation and subsequent premature entry into senescence. These data show that a loss of centrosomal integrity may contribute to the entry of MEFs into senescence in culture, and that centrosomal disruption can cause senescence.
Highlights
Cells normally possess stringent checkpoint mechanisms to ensure that they do not replicate with damaged DNA or other cellular abnormalities
In addition to proliferation arrest, some senescent cells become resistant to apoptotic death and most show morphological and metabolic changes, including cellular enlargement, increased lysosome biogenesis and atypical senescence-associated b-galactosidase activity (SA-b-gal).[4]
Senescence can be triggered by many events including DNA damage, telomere shortening, cell culture or oxidative stress, cytotoxic drugs, overexpression of tumor suppressor genes such as p53, or as a protective cellular response to strong mitogenic signaling by oncogenes.[5,6,7,8,9,10]
Summary
Cells normally possess stringent checkpoint mechanisms to ensure that they do not replicate with damaged DNA or other cellular abnormalities. Mouse embryonic fibroblasts (MEFs) are commonly used as a model to study cellular senescence These cells senesce as a result of oxidative stress in culture, which causes extensive DNA damage and resembles hydrogen peroxideinduced senescence in human cells, relying predominantly on the activation of p53 and p19ARF pathways.[14,15] To determine whether the centrosome contributes to senescence in MEFs, this study analyzed protein encoded by neural precursor cell expressed developmentally downregulated gene 1 (NEDD1), as a marker for the centrosome during senescence. Disrupting the centrosome in early-passage MEFs induced a loss of centrosome integrity and led to premature senescence, suggesting that centrosomes are involved in MEF senescence
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