Myriad signal transduction pathways instruct ge-nomes to transcribe genes. Insight into the signaling molecules converging on gene expression was accelerated in the 1980s with the discovery of numerous immediate early genes. The prototypic immediate early gene is c-fos, whose transcriptional regulation has been examined in intricate detail. Studies from the laboratories of Treisman, 1 Roeder, 2 and Weinberg3 defined an upstream c-fos enhancer that was responsive to several stimuli, including serum. The binding element was named serum response element and its core sequence (CCW6GG) constitutes what we know as a CArG box. The laboratory of Treisman subsequently cloned the serum response factor (SRF) and 1 of the first signaltranscription factorDNA binding element paradigms was established. 4 To date, 60 SRF-dependent genes exist in mammalian genomes and, of these, nearly half are restricted to muscle. 5 More than 100 hypothetical SRF-dependent genes await wet-laboratory validation (JMM, unpublished data, 2004).

Among signaling molecules, calcium stands as 1 with connections to virtually every biological process in nature, including gene transcription. Early studies showed an important role for calcium in the activation of c-fos transcription in neuronal cell types. Although several calcium channels could be linked to this process, it was the L-type voltage-sensitive calcium channel that was shown to be associated with c-fos induction. 6, 7 Misra et al showed the c-fos CArG element was calcium responsive through enhanced SRF binding following phosphorylation of Ser103 on SRF. 8 In vitro kinase assays verified SRF phosphorylation on Ser103 through calmodulin kinase IV, suggesting this calcium-dependent kinase was responsible for enhanced SRF binding to CArG and c-fos transcription. 8 Later studies revealed that cAMP response element-binding protein (CREB) recruits one of its coactivators, CBP (CREB-binding protein), following calmodulin kinase-dependent phosphorylation of CREB, leading to c-fos activation in hippocampal neurons. 9 Calcium-induced CBP recruitment to CREB likely lifts the repressive state of chromatin around the c-fos locus, permitting enhanced gene transcription.