Steroid Receptor Coactivator-2 Is a Dual Regulator of Cardiac Transcription Factor Function

• Published in: The Journal of biological chemistry Vol. 289; no. 25; pp. 17721 - 17731
• Main Authors: Reineke, Erin L., Benham, Ashley, Soibam, Benjamin, Stashi, Erin, Taegtmeyer, Heinrich, Entman, Mark L., Schwartz, Robert J., O'Malley, Bert W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-06-2014; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cardiac Metabolism; Gene Expression Regulation - physiology; Gene Regulation; Mice; Mice, Knockout; Muscle Proteins - genetics; Muscle Proteins - metabolism; Myocardium - cytology; Myocardium - metabolism; Nuclear Receptor Coactivator 2 - genetics; Nuclear Receptor Coactivator 2 - metabolism; Transcription Factor; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription Target Gene; Transcriptional Coactivator; Gene Regulation; Transcription Target Gene; Transcriptional Coactivator; Transcription Factor; Cardiac Metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.539908

We have previously demonstrated the potential role of steroid receptor coactivator-2 (SRC-2) as a co-regulator in the transcription of critical molecules modulating cardiac function and metabolism in normal and stressed hearts. The present study seeks to extend the previous information by demonstrating SRC-2 fulfills this role by serving as a critical coactivator for the transcription and activity of critical transcription factors known to control cardiac growth and metabolism as well as in their downstream signaling. This knowledge broadens our understanding of the mechanism by which SRC-2 acts in normal and stressed hearts and allows further investigation of the transcriptional modifications mediating different types and degrees of cardiac stress. Moreover, the genetic manipulation of SRC-2 in this study is specific for the heart and thereby eliminating potential indirect effects of SRC-2 deletion in other organs. We have shown that SRC-2 is critical to transcriptional control modulated by MEF2, GATA-4, and Tbx5, thereby enhancing gene expression associated with cardiac growth. Additionally, we describe SRC-2 as a novel regulator of PPARα expression, thus controlling critical steps in metabolic gene expression. We conclude that through regulation of cardiac transcription factor expression and activity, SRC-2 is a critical transcriptional regulator of genes important for cardiac growth, structure, and metabolism, three of the main pathways altered during the cardiac stress response.
Background: An efficient cardiac stress response requires a series of coordinated molecular changes.
Results: Steroid receptor coactivator-2 (SRC-2) controls the expression and activity of key cardiac transcription factors.
Conclusion: Dual regulation of cardiac transcription poises SRC-2 as a novel coordinator of the stress-responsive molecular network.
Significance: Identification of factors responsible for coordination of the cardiac stress response is critical for improved treatment.