Skip to main content
SpringerLink
Log in

E4BP4 is a cardiac survival factor and essential for embryonic heart development

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

The bZIP transcription factor E4BP4, has been demonstrated to be a survival factor in pro-B lymphocytes. GATA factors play important roles in transducing the IL-3 survival signal and transactivating the downstream survival gene, E4BP4. In heart, GATA sites are essential for proper transcription of several cardiac genes, and GATA-4 is a mediator of cardiomyocyte survival. However, the role E4BP4 plays in heart is still poorly understood. In this study, Dot-blot hybridization assays using Dig-labeled RNA probes revealed that the E4BP4 gene was expressed in cardiac tissue from several species including, monkey, dog, rabbit, and human. Western blot analysis showed that the E4BP4 protein was consistently present in all of these four species. Furthermore, immunohistochemistry revealed that the E4BP4 protein was overexpressed in diseased heart tissue in comparison with normal heart tissue. In addition, the overexpression of E4BP4 in vitro activated cell survival signaling pathway of cardiomyocytes. At last, siRNA-mediated knock down of E4BP4 in zebrafish resulted in malformed looping of the embryonic heart tube and decreased heart beating. Based on these results, we conclude that E4BP4 plays as a survival factor in heart and E4BP4 is essential for proper embryonic heart development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Cowell IG (2002) E4BP4/NFIL3, a PAR-related bZIP factor with many roles. Bioessays 24:1023–1029

    Article  CAS  PubMed  Google Scholar 

  2. Cowell IG, Skinner A, Hurst HC (1992) Transcriptional repression by a novel member of the bZIP family of transcription factors. Mol Cell Biol 12:3070–3077

    CAS  PubMed  Google Scholar 

  3. Zhang W, Zhang J, Kornuc M, Kwan K, Frank R, Nimer SD (1995) Molecular cloning and characterization of NF-IL3A, a transcriptional activator of the human interleukin-3 promoter. Mol Cell Biol 15:6055–6063

    CAS  PubMed  Google Scholar 

  4. Ikushima S, Inukai T, Inaba T, Nimer SD, Cleveland JL, Look AT (1997) Pivotal role for the NFIL3/E4BP4 transcription factor in interleukin 3-mediated survival of pro-B lymphocytes. Proc Natl Acad Sci USA 94:2609–2614

    Article  CAS  PubMed  Google Scholar 

  5. Yu YL, Chiang YJ, Yen JJY (2002) GATA factors are essential for transcription of the survival gene E4bp4 and the viability response of interleukin-3 in Ba/F3 hematopoietic cells. J Biol Chem 277:27144–27153

    Article  CAS  PubMed  Google Scholar 

  6. Yu YL, Chiang YJ, Chen YC, Papetti M, Juo CG, Skoultchi AI, Yen JJY (2005) MAPK-mediated phosphorylation of GATA-1 promotes Bcl-XL expression and cell survival. J Biol Chem 280:29533–29542

    Article  CAS  PubMed  Google Scholar 

  7. Metzstein MM, Hengartner MO, Tsung N, Ellis RE, Horvitz HR (1996) Transcriptional regulator of programmed cell death encoded by Caenorhabditis elegans gene ces-2. Nature 382:545–547

    Article  CAS  PubMed  Google Scholar 

  8. Lai CK, Ting LP (1999) Transcriptional repression of human hepatitis B virus genes by a bZIP family member, E4BP4. J Virol 73:3197–3209

    CAS  PubMed  Google Scholar 

  9. Nishimura Y, Tanaka T (2001) Calcium-dependent activation of NFIL3/E4BP4 gene expression by calcineurin/NFAT and CaM kinase signaling. J Biol Chem 276:19921–19928

    Article  CAS  PubMed  Google Scholar 

  10. Doi M, Nakajima Y, Okano T, Fukada Y (2001) Light-induced phase-delay of the chicken pineal circadian clock is associated with the induction of cE4bp4, a potential transcriptional repressor of cPer2 gene. Proc Natl Acad Sci USA 98:8089–8094

    Article  CAS  PubMed  Google Scholar 

  11. George H, Terracol R (1997) The vrille gene of Drosophila is a maternal enhancer of decapentaplegic and encodes a new member of the bZIP family of transcription factors. Genetics 146:1345–1363

    CAS  PubMed  Google Scholar 

  12. Cowell IG, Hurst HC (1994) Transcriptional repression by the human bZlP factor E4BP4: definition of a minimal repression domain. Nucleic Acids Res 22:59–65

    Article  CAS  PubMed  Google Scholar 

  13. Cowell IG, Hurst HC (1996) Protein-protein interaction between the transcriptional repressor E4BP4 and the TBP-binding protein Dr1. Nucleic Acids Res 24:3607–3613

    Article  CAS  PubMed  Google Scholar 

  14. Suzuki YJ, Evans T (2004) Regulation of cardiac myocyte apoptosis by the GATA-4 transcription factor. Life Sci 74:1829–1838

    Article  CAS  PubMed  Google Scholar 

  15. Park GH, Buetow DE (1991) Genes for insulin-like growth factors I and II are expressed in senescent rat tissues. Gerontology 37:310–316

    Article  CAS  PubMed  Google Scholar 

  16. Huang CY, Kasai M, Buetow DE (1998) Extremely-rapid RNA detection in dot blots with digoxigenin-labeled RNA probes. Genet Anal 4:109–112

    Google Scholar 

  17. Fraysse B, Mons R, Garric J (2006) Development of a zebrafish 4-day embryo-larval bioassay to assess toxicity of chemicals. Ecotoxicol Environ Saf 63:253–267

    Article  CAS  PubMed  Google Scholar 

  18. Carney SA, Prasch AL, Heideman W (2006) Understanding dioxin developmental toxicity using the zebrafish model. Birth Defects Res A Clin Mol Teratol 76:7–18

    Article  CAS  PubMed  Google Scholar 

  19. Barut B, Zon LI (2000) Realizing the potential of zebrafish as a model for human disease. Physiol Genomics 2:49–51

    CAS  PubMed  Google Scholar 

  20. Langheinrich U, Zebrafish (2003) A new model on the pharmaceutical catwalk. Bioessays 25:904–912

    Article  CAS  PubMed  Google Scholar 

  21. Spitsbergen JM, Kent ML (2003) The state of the art of the zebrafish model for toxicology and toxicologic pathology research-advantages and current limitations. Toxicol Pathol 31:62–87

    CAS  PubMed  Google Scholar 

  22. Hill AJ, Teraoka H, Heideman W, Peterson RE (2005) Zebrafish as a model vertebrate for investigating chemical toxicity. Toxicol Sci 86:6–19

    Article  CAS  PubMed  Google Scholar 

  23. Kimmel CB, Ballard WW, Kimmel SR, Ullmann B, Schilling TF (1995) Stages of embryonic-development of the zebrafish. Dev Dyn 203:253–310

    CAS  PubMed  Google Scholar 

  24. Burggren WW (2004) What is the purpose of the embryonic heart beat? Or how facts can ultimately prevail over physiological dogma. Physiol Biochem Zool 77:333–345

    Article  PubMed  Google Scholar 

  25. McCormick KM, Dahms NM, Lough J (1996) Insulin-like growth factor-II/mannose-6-phosphate receptor expression during early heart development. Dev Dyn 207:195–203

    Article  CAS  PubMed  Google Scholar 

  26. Bikle DD, Harris J, Halloran BP, Roberts CT, Leroith D, Morey-Holton E (1994) Expression of the genes for insulin-like growth factors and their receptors in bone during skeletal growth. Am J Physiol 267:E278–E286

    CAS  PubMed  Google Scholar 

  27. Meng A, Tang H, Yuan B, Ong BA, Long Q, Lin S (1999) Positive and negative cis-acting elements are required for hematopoietic expression of zebrafish GATA-1. Blood 93:500–508

    CAS  PubMed  Google Scholar 

  28. Eckfeldt CE, Mendenhall EM, Flynn CM, Wang TF, Pickart MA, Grindle SM, Ekker SC, Verfaillie CM (2005) Functional analysis of human hematopoietic stem cell gene expression using zebrafish. PLoS Biol 3:e254

    Article  PubMed  Google Scholar 

  29. Burke AP, Virmani R (2007) Pathophysiology of acute myocardial infarction. Med Clin North Am 91:553–572

    Article  PubMed  Google Scholar 

  30. Gupta KB, Ratcliffe MB, Fallert MA, Edmunds LH Jr, Bogen DK (1994) Changes in passive mechanical stiffness of myocardial tissue with aneurysm formation. Circulation 89:2315–2326

    CAS  PubMed  Google Scholar 

  31. Pfeffer JM, Pfeffer MA, Fletcher PJ, Braunwald E (1991) Progressive ventricular remodeling in rat with myocardial infarction. Am J Physiol Heart Circ Physiol 260:H1406–H1414

    CAS  Google Scholar 

  32. Raya TE, Gay RG, Lancaster L, Aguirre M, Moffett C, Goldman S (1988) Serial changes in left ventricular relaxation and chamber stiffness after large myocardial infarction in rats. Circulation 77:1424–1431

    CAS  PubMed  Google Scholar 

  33. Paul S (2003) Ventricular remodeling. Crit Care Nurs Clin North Am 15:407–411

    Article  PubMed  Google Scholar 

  34. Samarel AM (2002) IGF-1 overexpression rescues the failing heart. Circ Res 90:631–633

    Article  CAS  PubMed  Google Scholar 

  35. Kinoshita T, Yokota T, Arai K, Miyajima A (1995) Suppression of apoptotic death in hematopoietic cells by signaling through the IL-3/GMCSF receptors. EMBO J 14:266–275

    CAS  PubMed  Google Scholar 

  36. Kinoshita T, Shirouzu M, Kamiya A, Hashimoto K, Yokoyama S, Miyajima A (1997) Raf/MAPK and rapamycin-sensitive pathways mediate the anti-apoptotic function of p21 Ras in IL-3-dependent hematopoietic cells. Oncogene 15:619–627

    Article  CAS  PubMed  Google Scholar 

  37. Junghans D, Chauvet S, Buhler E, Dudley K, Sykes T, Henderson CE (2004) The CES-2-related transcription factor E4BP4 is an intrinsic regulator of motoneuron growth and survival. Development 131:4425–4434

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

We greatly appreciate Dr Jeffrey J. Y. Yen (Institute of Biomedical Sciences, Academia Sinica, Taiwan) for providing the E4BP4 plasmids.

Author information

Authors and Affiliations

  1. Department of Veterinary Medicine, National Chung-Hsing University, No.250, Kuo-Kuang Road, 402, Taichung, Taiwan

    Yi-Jiun Weng & Kwong-Chung Tung

  2. School of Medical Laboratory and Biotechnology, Chung-Shan Medical University, 402, Taichung, Taiwan

    Dennis Jine-Yuan Hsieh

  3. Department of Biological Science and Technology, China Medical University, Taichung, Taiwan

    Wei-Wen Kuo

  4. School of Post-Baccalaureate Chinese Medicine, China Medical University, 404, Taichung, Taiwan

    Tung-Yuan Lai

  5. Division of Colorectal Surgery, Mackay Memorial Hospital, Taipei, Taiwan

    Hsi-Hsien Hsu

  6. Mackay Medicine, Nursing and Management College, Taipei, Taiwan

    Hsi-Hsien Hsu

  7. Department of Healthcare Administration, Asia University, Taichung, Taiwan

    Chang-Hai Tsai

  8. Graduate Institute of Chinese Medical Science, China Medical University, 404, Taichung, Taiwan

    Fuu-Jen Tsai & Chih-Yang Huang

  9. Graduate Institute of Basic Medical Science, China Medical University, 404, Taichung, Taiwan

    Ding-Yu Lin, James A. Lin & Chih-Yang Huang

  10. Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan

    Chih-Yang Huang

Authors
  1. Yi-Jiun Weng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dennis Jine-Yuan Hsieh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei-Wen Kuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tung-Yuan Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hsi-Hsien Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chang-Hai Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fuu-Jen Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ding-Yu Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. James A. Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chih-Yang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kwong-Chung Tung
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kwong-Chung Tung.

Additional information

James A. Lin, Chih-Yang Huang, and Kwong-Chung Tung contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 92 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weng, YJ., Hsieh, D.JY., Kuo, WW. et al. E4BP4 is a cardiac survival factor and essential for embryonic heart development. Mol Cell Biochem 340, 187–194 (2010). https://doi.org/10.1007/s11010-010-0417-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-010-0417-6

Keywords

Search

Navigation