The signal transduction pathways that control cell cycle progression also function in mediating apoptotic neuronal death. Thus, DNA damage increases the activity of cdk4/6 and the pRb/E2F/DP proteins, and blocking this pathway inhibits cell death. Levels of cdk4/6 are unchanged, while cyclin D1 levels are increased, suggesting that the increase in cdk activity is due to upregulation of cyclin D1. In this report, we have investigated the signal transduction pathway that leads to the upregulation of cyclin D1 in neurons following UV irradiation. Dissociated cultures of postnatal day 8 rat cerebellar granule neurons were exposed to UV irradiation after 24 hr in culture. Levels of cyclin D1 protein and mRNA are increased within one hr after irradiation. Because cyclin D1 has been shown to be transcriptionally regulated by c-Jun/AP-1, and because stress activated kinases are involved in the response to DNA damage, we hypothesized that this pathway could also be involved after DNA damage in neurons following UV irradiation. C-Jun and its activated form, phospho c-Jun, were both significantly increased in cerebellar granule cells after UV exposure. Both curcumin and quercetin reduced granule cell death and reduced both c-Jun and cyclin D1 activation. Overexpression of the JNK binding domain (JBD) of JIP-1, which acts as a potent inhibitor of the JNK signal transduction pathway also resulted in a reduction of cell death and c-Jun and cyclin D1 upregulation. Thus, upregulation of cyclin D1 through activation of c-Jun and the activation of cdks are essential for apoptosis after DNA damage.