MSK2 Inhibits p53 Activity in the Absence of Stress

The kinase MSK2 inhibits p53 transcriptional activity at a subset of promoters through a kinase-independent mechanism. Kinase Activity Not Required The tumor suppressor p53, which mediates transcriptional responses to DNA damage, is encoded by one of the genes most frequently mutated in cancer cells. Its activity can be regulated by various binding partners, including the mitogen- and stress-activated kinase 2 (MSK2). Although MSK2 regulates the activity of other transcription factors through phosphorylation, Llanos et al. show that inhibition of p53 by MSK2 does not require its catalytic activity. p53 transcriptional activity was inhibited by an MSK2 mutant that lacked both of its kinase domains. MSK2 inhibited basal p53 activity at select promoters by reducing the activity of the histone deacetylase p300, which coactivates p53. Specific apoptotic stimuli led to MSK2 degradation, enabling p53-mediated induction of the pro-apoptotic protein Noxa. Thus, these results delineate a kinase-independent function for MSK2 and a new pathway whereby the activity of p53 can be regulated. Mitogen- and stress-activated kinase 2 (MSK2) inhibits the transcription factor p53, and we investigate here the mechanisms underlying this inhibition. In the absence of stress stimuli, MSK2 selectively suppressed the expression of a subset of p53 target genes. This basal inhibition of p53 by MSK2 occurred independently of its kinase activity and of upstream mitogen-activated protein kinase signaling to MSK2. Furthermore, MSK2 interacted with and inhibited the p53 coactivator p300 and associated with the Noxa promoter. Apoptotic stimuli promoted the degradation of MSK2, thus relieving its inhibition of p53 and enabling efficient p53-dependent transactivation of Noxa, which contributed to apoptosis. Together, these findings constitute a new mechanism for the regulation of p53 transcriptional activity in response to stress.