Oncogene-induced senescence is a stable proliferative arrest that serves as a 
tumor-suppressing defense mechanism. p38 mitogen-activated protein kinase (MAPK) 
has been implicated in oncogene-induced senescence and tumor suppression. 
However, the specific role of each of the four p38 isoforms in oncogene-induced 
senescence is not fully understood. Here, we demonstrate that p38δ mediates 
oncogene-induced senescence through a p53- and p16(INK4A)-independent mechanism. 
Instead, evidence suggests a link between p38δ and the DNA damage pathways. 
Moreover, we have discovered a novel mechanism that enhances the expression of 
p38δ during senescence. In this mechanism, oncogenic ras induces the 
Raf-1-MEK-extracellular signal-regulated kinase (ERK) pathway, which, in turn, 
activates the AP-1 and Ets transcription factors that are bound to the p38δ 
promoter, leading to increased transcription of p38δ. These findings indicate 
that induction of the prosenescent function of p38δ by oncogenic ras is achieved 
through 2 mechanisms, transcriptional activation by the Raf-1-MEK-ERK-AP-1/Ets 
pathway, which increases the cellular concentration of the p38δ protein, and 
posttranslational modification by MKK3/6, which stimulates the enzymatic 
activity of p38δ. In addition, these studies identify the AP-1 and Ets 
transcription factors as novel signaling components in the senescence-inducing 
pathway.