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(Circulation Research. 2004;95:340.)
© 2004 American Heart Association, Inc.

Editorials

Channeling to Myocardin

Joseph M. Miano

From the Center for Cardiovascular Research in the Aab Institute of Biomedical Sciences, University of Rochester School of Medicine, Rochester, NY.

Correspondence to Joseph M. Miano, Department of Medicine, University of Rochester School of Medicine, 601 Elmwood Ave, Rochester, NY 14642. E-mail j.m.miano@rochester.edu

Key Words: signal transduction • gene regulation • smooth muscle • serum response factor • myocardin

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Myriad signal transduction pathways instruct genomes 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 signal>transcription factor>DNA 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half are restricted to muscle.⁵ More than 100 hypothetical SRF-dependent genes await wet-laboratory validation (J.M.M., unpublished data, 2004).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 . . . [Full Text of this Article]

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