| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
E-mail contact: qliang{at}usd.edu
The transcription factor GATA-4 protects cardiomyocytes against doxorubicin-induced cardiotoxicity. Here, we report the identification of Bcl2 as a direct target gene of GATA4 that may mediate the prosurvival function of GATA4 in cardiomyocytes. Bcl2 transcript and protein levels were reduced by doxorubicin in neonatal rat ventricular cardiomyocytes (NRVC) and in mouse heart as determined by RT-PCR and Western blot analysis. The reduction in Bcl2 was prevented by overexpression of GATA4 in NRVC and in transgenic mouse heart. Also, expression of GATA4 increased baseline Bcl2 levels by 30% in NRVC and 2.7-fold in transgenic heart, indicating the sufficiency of GATA4 to up-regulate Bcl2 gene expression. GATA4 knockdown by siRNA reduced Bcl2 levels by 48% in NRVC, suggesting that GATA4 is required for Bcl2 constitutive gene expression. Transfection of HEK cells with GATA4 plasmids activated Bcl2 promoter and elevated Bcl2 protein levels. Deletion and mutagenesis analysis revealed that a consensus GATA motif at base -266 on the promoter conserved across multiple species is partially responsible for the promoter activity. Electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrate that GATA4 directly bound to this GATA site. Together, these results indicate that GATA4 positively regulates cardiac Bcl2 gene expression in vitro and in vivo.
Key words: cardiomyocyte • promoter • doxorubicin • cardiotoxicity
This article has been cited by other articles:
|
|
 |
|
  Y. Huang, C. D. Wright, S. Kobayashi, C. L. Healy, M. Elgethun, A. Cypher, Q. Liang, and T. D. O'Connell GATA4 is a survival factor in adult cardiac myocytes but is not required for {alpha}1A-adrenergic receptor survival signaling Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H699 - H707. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Viger, S. M. Guittot, M. Anttonen, D. B. Wilson, and M. Heikinheimo Role of the GATA Family of Transcription Factors in Endocrine Development, Function, and Disease Mol. Endocrinol., April 1, 2008; 22(4): 781 - 798. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zurney, K. E. Howard, and B. Sherry Basal Expression Levels of IFNAR and Jak-STAT Components Are Determinants of Cell-Type-Specific Differences in Cardiac Antiviral Responses J. Virol., December 15, 2007; 81(24): 13668 - 13680. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Yin, Z. Lin, Y.-H. Cheng, E. E. Marsh, H. Utsunomiya, H. Ishikawa, Q. Xue, S. Reierstad, J. Innes, S. Thung, et al. Progesterone Receptor Regulates Bcl-2 Gene Expression through Direct Binding to Its Promoter Region in Uterine Leiomyoma Cells J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4459 - 4466. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. G. Neilan, S. L. Blake, F. Ichinose, M. J. Raher, E. S. Buys, D. S. Jassal, E. Furutani, T. M. Perez-Sanz, A. Graveline, S. P. Janssens, et al. Disruption of Nitric Oxide Synthase 3 Protects Against the Cardiac Injury, Dysfunction, and Mortality Induced by Doxorubicin Circulation, July 31, 2007; 116(5): 506 - 514. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kobayashi, K. Mao, H. Zheng, X. Wang, C. Patterson, T. D. O'Connell, and Q. Liang Diminished GATA4 Protein Levels Contribute to Hyperglycemia-induced Cardiomyocyte Injury J. Biol. Chem., July 27, 2007; 282(30): 21945 - 21952. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Bian, Z. B. Popovic, C. Benejam, M. Kiedrowski, L. L. Rodriguez, and M. S. Penn Effect of Cell-Based Intercellular Delivery of Transcription Factor GATA4 on Ischemic Cardiomyopathy Circ. Res., June 8, 2007; 100(11): 1626 - 1633. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
