Fig. 6.

Summary of signaling events leading to PRKD2-dependent induction of senescence in p53^wt and p53^mut GBM cells. RTK and/or GPCR signaling induces PKCs and downstream PRKD2 activation. Silencing of PRKD2 attenuates AKT activation (and MAPK activation in U87MG cells). In p53^wt U87MG and primary GBM2 cells, this leads to increased p53, p21, and p27 expression. As a consequence, diminished cyclin-CDK activation, hypophosphorylation of pRb, and reduced transcription of E2F target genes induce senescence. In p53^mut GM133 and Gli25 primary cells, PRKD2 silencing results in decreased AKT activation, upregulation of p15 and p27, G1/S arrest, and downregulated E2F1 transcription. Also this pathway induces senescence; however, the signaling modules downstream of p15 and p27 that are ultimately responsible for the induction of senescence remain to be elucidated.