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(Circulation Research. 2004;94:1492.)
© 2004 American Heart Association, Inc.

Molecular Medicine

Endothelin-1–Dependent Nuclear Factor of Activated T Lymphocyte Signaling Associates With Transcriptional Coactivator p300 in the Activation of the B Cell Leukemia-2 Promoter in Cardiac Myocytes

Teruhisa Kawamura, Koh Ono, Tatsuya Morimoto, Masaharu Akao, Eri Iwai-Kanai, Hiromichi Wada, Naoya Sowa, Toru Kita, Koji Hasegawa

From the Department of Cardiovascular Medicine (T Kawamura, T.M., M.A., E.I.-K., H.W., N.S., T Kita), Graduate School of Medicine, Kyoto University, Kyoto, Japan; Division of Translational Research (K.O., K.H.), Kyoto Medical Center, National Hospital Organization, Kyoto, Japan.

Correspondence to Koji Hasegawa, MD, PhD, Division of Translational Research, Kyoto Medical Center, National Hospital Organization, 1-1 Mukaihata-cho Fukakusa, Fushimi-ku, Kyoto 612-8555, Japan. E-mail koj{at}kuhp.kyoto-u.ac.jp

Endothelin-1 (ET-1) is a potent survival factor that protects cardiac myocytes from apoptosis. ET-1 induces cardiac gene transcription and protein expression of antiapoptotic B cell leukemia-2 (bcl-2) in a calcineurin-dependent manner. A cellular target of adenovirus early region 1A (E1A) oncoprotein, p300 also activates bcl-2 transcription in cardiac myocytes and is required for their survival. p300 acts as a calcineurin-regulated nuclear factors of activated T lymphocytes (NFATc), downstream targets of calcineurin. In addition, the bcl-2 promoter contains multiple NFAT consensus sequences. These findings prompted us to investigate the role of NFATc in ET-1–dependent and p300-dependent bcl-2 transcription in cardiac myocytes. In primary cardiac myocytes prepared from neonatal rats, mutation of 2 NFAT sites within the bcl-2 promoter completely abolished the ET-1– and p300-induced increases in the activity of this promoter. We show here that p300 markedly potentiates the binding of NFATc1 to the bcl-2 NFAT element by interacting with NFATc1 in an E1A-dependent manner. On the other hand, stimulation of cardiac myocytes with ET-1 causes nuclear translocation of NFATc1, which interacts with p300 and increases DNA binding. Expression of E1A did not change the cardiac nuclear localization of NFATc1 but blocked its interaction with p300, DNA binding, and bcl-2 promoter activation. These findings suggest that ET-1–dependent NFATc signaling associates with p300 in the transactivation of bcl-2 gene in cardiac myocytes.

Key Words: transcription • calcineurin • NFAT • endothelin-1 • cardiomyocytes

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