We previously demonstrated that protein kinase C␦ (PKC␦; PKC delta) is an oxidative stress-sensitive kinase that plays a causal role in apoptotic cell death in neuronal cells. Although PKC␦ activation has been extensively studied, relatively little is known about the molecular mechanisms controlling PKC␦ expression. To characterize the regulation of PKC␦ expression, we cloned an ϳ2-kbp 5-promoter segment of the mouse Prkcd gene. Deletion analysis indicated that the noncoding exon 1 region contained multiple Sp sites, including four GC boxes and one CACCC box, which directed the highest levels of transcription in neuronal cells. In addition, an upstream regulatory region containing adjacent repressive and anti-repressive elements with opposing regulatory activities was identified within the region ؊712 to ؊560. PKC represents a large family of at least 12 serine/threonine kinases that participate in a wide variety of cellular events, including proliferation, cell cycle progression, differentiation, and apoptosis (1). Based on their structure and substrate requirements, PKC isoforms are divided into the following three groups: conventional PKCs (␣, I, II, and ␥), novel PKCs (␦, ⑀, , and ), and atypical PKCs ( and /). As a novel PKC, PKC␦ has been recognized as a key pro-apoptotic effector in various cell types (2, 3). The role of PKC␦ in nervous system function is beginning to emerge, and recent studies show that PKC␦ plays a role in regulation of receptor and channel activity, differentiation, migration, and apoptosis (4). In addition to lipid-mediated activation and phosphorylation activation, a new pathway of PKC␦ activation, proteolytic cleavage, was discovered recently. Previously, we showed that PKC␦ is an oxidative stress-sensitive kinase and that persistent activation of PKC␦ by caspase-3-mediated proteolytic cleavage is a key mediator in oxidative stress-induced dopaminergic neurodegeneration (5-9). Alternatively, pharmacological inhibition of PKC␦ and depletion of PKC␦ by siRNA are each sufficient to prevent dopaminergic neurodegeneration in cell culture and animal models of Parkinson disease (10 -12). We also showed that PKC␦ negatively regulates tyrosine hydroxylase activity and dopamine synthesis by enhancing protein phosphatase 2A activity in dopaminergic neurons (13). An elevated striatal dopamine level was observed in PKC␦ knock-out mice as compared with wild-type mice, further demonstrating a key role of the kinase in the nigrostriatal dopaminergic function (13). In addition, increased PKC␦ activity, caused by aberrant expression of PKC␦, has been implicated in disease conditions, such as ischemia/hypoxia (14 -17) and cancer (18 -28). Therefore, an understanding of the molecular mechanisms that control the amount and activity of PKC␦ is of physiological and pathophysiological interest.PKC␦ is ubiquitously expressed although the expression pattern is varied and complex (29 -32). Evidence suggests that diverse stimuli can induce PKC␦ expression (33)(34)(35)(37)(38)(39), but the detailed mechanisms...