A Low-Affinity Serum Response Element Allows Other Transcription Factors To Activate Inducible Gene Expression in Cardiac Myocytes

Abstract

Hypertrophic growth of cardiac muscle cells is induced by a variety of physiological and pathological stimuli and is associated with a number of changes, including activation of genes such as atrial natriuretic factor. We found that two serum response element (SRE)-like DNA elements, one of which does not meet the consensus sequence and binds serum response factor (SRF) with low affinity, regulate the activity of this promoter. Surprisingly, the ability to induce the promoter by two different physiologic stimuli, as well as various activated transcription factors, including SRF-VP16, was primarily dependent upon the nonconsensus rather than the consensus SRE. This SRE controls the induction of gene expression via an unusual mechanism in that it is required to allow some, but not all, active transcription factors at unrelated sites on the promoter to stimulate gene expression. Thus, in addition to regulation of SRF activity by growth stimuli, regulation of a low-affinity SRE element controls inducible gene expression by modulating the ability of other transcription factors to stimulate the transcription machinery.

ACKNOWLEDGMENTS

We are grateful to the various colleagues who provided plasmids that were used in this work. We thank Jamie Coombs for help with several of these experiments and Don Ayer and Steve Prescott for comments on the manuscript.

This research was supported by NIH grant HL 52010, the Thomas D. Dee Fellowship in Human Genetics (W.A.H.), and funds from the Huntsman Cancer Institute and was completed in partial fulfillment of the Ph.D. degree in Human Genetics (W.A.H.).