CALCIUM CALMODULIN-DEPENDENT PROTEIN-KINASE TYPE-II AND TYPE-IV DIFFERENTIALLY REGULATE CREB-DEPENDENT GENE-EXPRESSION/

Phosphorylation of CREB (cyclic AMP [cAMP]- response element [CRE]-bin ding protein) by cAMP-dependent protein kinase (PKA) leads to the acti vation of many promoters containing CREs. In neurons and other cell ty pes, CREB phosphorylation and activation of CRE containing promoters c an occur in response to elevated intracellular Ca2+ In cultured cells that normally lack this Ca2+ responsiveness, we confer Ca2+-mediated a ctivation of a CRE containing promoter by introducing an expression ve ctor for Ca2+/calmodulin-dependent protein kinase type IV (CaMKIV). Ac tivation could also be mediated directly by a constitutively active fo rm of CaMKIV which is Ca2+ independent. The CaMKIV-mediated gene induc tion requires the activity of CREB/ATF family members but is independe nt of PKA activity. In contrast, transient expression of either a cons titutively active or wild-type Ca2+/calmodulin-dependent protein kinas e type II (CaMKII) fails to mediate the transactivation of the same CR E-containing reporter gene. Examination of the subcellular distributio n of transiently expressed CaMKIV and CaMKII reveals that only CaMKIV enters the nucleus. Our results demonstrate that CaMKIV, which is expr essed in neuronal, reproductive, and lymphoid tissues, may act as a me diator of Ca2+-dependent gene induction.