Transcription of the protein kinase C-δ gene is activated by JNK through c-Jun and ATF2 in response to the anticancer agent doxorubicin

Expression of protein kinase C-δ (PKCδ) is up-regulated by apoptosis-inducing stimuli. However, very little is known about the signaling pathways that control PKCδ gene transcription. In the present study, we demonstrate that JNK stimulates PKCδ gene expression via c-Jun and ATF2 in response to the anticancer agent doxorubicin (DXR) in mouse lymphocytic leukemia L1210 cells. Luciferase reporter assays showed that DXR-induced activation of the PKCδ promoter was enhanced by ectopic expression of JNK1, c-Jun, or ATF2, whereas it was strongly reduced by expression of dominant negative JNK1 or by treatment with the JNK inhibitor SP600125. Furthermore, point mutations in the core sequence of the c-Jun/ATF2 binding site suppressed DXR-induced activation of the PKCδ promoter. Our results suggest an additional role for a JNK signaling cascade in DXR-induced PKCδ gene expression.