Calcium activates serum response factor-dependent transcription by a Ras- and Elk-1-independent mechanism that involves a Ca²⁺/calmodulin-dependent kinase

Enhanced levels of cytoplasmic Ca²⁺ due to membrane depolarization with elevated levels of KCl or exposure to the Ca²⁺ ionophore ionomycin stimulate serum response element (SRE)-dependent transcription in the pheochromocytoma cell line PC12. By using altered binding specificity mutants of transcription factors that bind to the SRE, it was demonstrated that in contrast to treatment with purified growth factors, such as nerve growth factor, the serum response factor (SRF), but not Elk-1, mediates Ca²⁺- regulated SRE-dependent transcription. Enhanced levels of cytoplasmic Ca²⁺ were found to trigger SRE-dependent transcription via a Ras-independent signaling pathway that appears to involve a Ca²⁺/calmodulin-dependent kinase (CaMK). Overexpression of a constitutively active form of CaMKIV stimulated SRF-dependent transcription. Taken together, these findings indicate that SRF is a versatile transcription factor that, when bound to the SRE, can function by distinct mechanisms and can mediate transcriptional responses to both CaMK- and Ras-dependent signaling pathways.