Transcriptome analysis and tumor suppressor requirements of STAT5-induced senescence.

Although it is acknowledged that senescent cells accumulate with age, the molecular mechanisms leading to cell senescence as a function of age remain to be identified. In cell culture models, it has been clearly shown that senescence involves the activation of a DNA damage response secondary to short telomeres or oncogene expression. Oncogenes are altered versions of genes coding for proteins that mediate signals from extracellular factors such as cytokines, growth factors, and hormones. In particular, we show here that constitutive activation of the JAK/STAT5 signaling pathway induces senescence in both mouse and human normal cells. The process involves activation of the p53 and Rb tumor suppressor pathways and mitochondrial dysfunction. Gene expression analysis of STAT5-induced senescence revealed changes in the expression of genes coding for cytokines, proteins in cytokine signaling pathways, and several metabolic enzymes. We discuss a model called senescence-induced senescence, in which cytokines secreted by senescent cells can propagate the process as a function of age.