The protein kinase CK2 (casein kinase 2) is a ubiquitous serine/threonine protein kinase that suppresses apoptosis. CK2 is composed of catalytic and regulatory subunits, and CK2-dependent phosphorylation is a global mechanism in the inhibition of caspase signaling pathways. The serum response factor (SRF) is an important regulator of cell growth and differentiation. Although CK2 has been shown to phosphorylate SRF in vitro, the biological relevance of this interaction remains largely unclear. We observed increased SRF phosphorylation and increased Mcl-1 gene expression in hippocampal CA1 neurons following transfection with a plasmid expressing the wild-type CK2α (CK2αWT) protein, whereas transfection with a plasmid expressing a catalytically inactive mutant of CK2α (CK2α156A) reduced Mcl-1 gene expression. Cotransfection with a plasmid expressing the inactive SRF99A mutant inhibited the CK2αWT-induced upregulation of Mcl-1 gene expression. The expression of either the CK2α156A or the SRF99A mutant also inhibited the glutamate-induced upregulation of Mcl-1 protein expression in PC12 cells. Our results suggest that CK2-mediated signaling represents a cellular mechanism that may aid in the development of alternative therapeutic strategies to attenuate apoptosis in hippocampal neurons.