Abstract
Hypertrophic stimulation of cardiac myocytes results in rapid induction of a number of transcription factors, including members of the AP-1 family, which is followed by a programmed alteration in the pattern of gene expression. In the ventricular cardiocytes there is re-expression of the fetal atrial natriuretic factor (ANF) gene and upregulation of its myosin light chain-2 (MLC-2v). The mechanism(s) by which the induction of AP-1 is coupled to the promoters of these target genes is largely unknown. In this report, we demonstrate that in transient co-transfection assay, c-Jun inhibited while Jun B stimulated the MLC-2v promoter activity. Mutant c-Jun recombinants, in which the activation domains were deleted, still remained inhibitory, but a specific mutation in the leucine zipper, which changes the alignment of Jun with its dimerization partner, caused a reversal of its effect on the target MLC-2v promoter. Based on these findings, we propose that in chicken cardiac myocytes, the regulation of MLC-2v promoter by Jun may occur via its interaction with other proteins, possibly of the leucine zipper family.
Similar content being viewed by others
References
Chien KR, Knowlton KU, Zhu H, Chien S: Regulation of cardiac gene expression during myocardial growth and hypertrophy: Molecular studies on an adaptive physiological response. FASEB J 5: 3037–3046, 1991
Parker TG: Molecular biology of myocardial hypertrophy and failure: Gene expression and trophic signaling. New Horizons 3: 288–300, 1995
Sadoshima J, Izumo S: Signal transduction pathways of angiotensin II-induced c-fos gene expression in cardiac myocytes in vitro. Circ Res 73: 424–438, 1993
Shubeita HE, Martinson EA, Van Bilsen M, Chien KR, Brown JH: Transcriptional activation of the cardiac myosin light chain 2 and atrial natriuretic factor genes by protein kinase C in neonatal rat ventricular myocytes. Proc Natl Acad Sci 89: 1305–1309, 1992
Iawaki K, Sukhatme VP, Shubeita HE, Chien KR: α-and β-adrenergic stimulation induces distinct patterns of immediate gene expression in neonatal rat myocardial cells. J Biol Chem 265: 13809–13817, 1990
Paradis P, MacLellan WR, Belaguli NS, Schwartz RJ, Schneider MD: Serum response factor mediates AP-1 dependent induction of the skeletal α-actin promoter in ventricular myocytes. J Biol Chem 271: 10827–10833, 1996
Kovacic-Milivojevic B, Gardner DG: Fra-1, A Fos gene family member that activates atrial natriuretic peptide gene transcription. Hypertension 25: 679–682, 1995
McBride K, Robitaille L, Tremblay S, Argentin S, Nemer M: Fos/Jun repression of cardiac specific transcription in quiescent and growth stimulated myocytes is targeted at a tissue specific cis element. Mol Cell Biol 13: 600–612, 1993
Knowlton KU, Baracchini E, Ross RS, Harris AN, Henderson SA, Evans SM, Glembotski CC, Chein KR: Coregulation of the atrial natriuretic factor and cardiac myosin light chain-2 genes during α-adrenergic stimulation of neonatal rat ventricular cells. J Biol Chem 266: 7759–7768, 1991
Zheng JS, Boluyt MO, Long X, O'Neill L, Lakatta EG, Crow MT: Extracellular ATP inhibits adrenergic agonist-induced hypertrophy of neonatal cardiac myocytes. Circ Res 78: 525–535, 1996
Bishoprick NH, Jayasena V, Webster KA: Positive regulation of the skeletal α-actin gene by Fos and Jun in cardiac myocytes. J Biol Chem 267: 2535–25540, 1992
Kovacic-Milivojevic B, Gardner DG: Divergent regulation of the human atrial natriuretic peptide gene by c-Jun and c-Fos. Mol Cell Biol 12: 292–301, 1992
Zheng JS, Boluyt MO, O'Neill L, Crow MT, Lakatta EG: Extracellular ATP induces immediate early gene expression but not cellular hypertrophy in neonatal cardiac myocytes. Circ Res 74: 1034–1041, 1994
Karin M, Liu ZG, Zandi E: AP-1 function and regulation. Curr Opin Cell Biol 9: 240–246, 1997
Claret FX, Hibi M, Dhut S, Toda T, Karin MA: A new group of conserved co-activators that increase the specificity of AP-1 transcription factors. Nature 383: 453–457, 1996
Bannister AJ, Oehler T, Wilhelm D, Angel P, Kouzarides T: Stimulation of c-Jun activity by CBP: c-Jun residues Ser 63/73 are required for CBP induced stimulation in vivo and CBP binding in vitro. Oncogene 11: 2509–2514, 1995
Bois-Joyeux B, Denissenko M, Thomassin H, Guesdon S, Ikonomova R, Bernuau D, Feldman G, Danan JL: The c-Jun proto-oncogene down-regulates the rat α-fetoprotein promoter in hepG2 hepatoma cells without binding to DNA. J Biol Chem 270: 10204–10211, 1995
Schaefer TS, Sanders LK, Nathans D: Cooperative transcriptional activity of Jun and Stat 3B, a short form of Stat 3. Proc Natl Acad Sci 92: 97–9101, 1995
Hsu W, Kerppola TK, Chen PI, Curran T, Chen-Kiang S: Fos and Jun repress transcription activation by NF-IL6 through association at the basic zipper region. Mol Cell Biol 14: 268–276, 1994
Monteclaro FS, Vogt P: A Jun-binding protein related to a putative tumor Suppressor. Proc Natl Acad Sci 90: 6726–6730, 1993
Bengal E, Ransone L, Scharfmann R, Dwarki VJ, Tapscott SJ, Weintraub H, Verma IM: Functional antagonism between c-Jun and MyoD proteins: A direct physical association. Cell 68: 507–519, 1992
Li L, Chambard JC, Karin M, Olson EN: Fos and Jun repress transcriptional activation by myogenin and MyoD: The amino terminus of Jun mediates repression. Genes Dev 6: 676–689, 1992
Goswami S, Qasba P, Ghatpande S, Carleton S, Deshpande AK, Baig M, Siddiqui MAQ: Differential expression of the myocyte enhancer factor 2 family of transcription factors in development: The cardiac factor BBF-1 is an early marker for cardiogenesis. Mol Cell Biol 14: 5130–5138, 1994
Bolyut MO, O'Neill L, Meredith AL, Bing OHL, Brooks WW, Conrad CH, Crow MT, Lakatta EG: Alterations in cardiac gene expression during the transition from stable hypertrophy to heart failure. Circ Res 75: 23–32, 1994
Doud SK, Pan LX, Carleton S, Mamorstein S, Siddiqui S: Adaptational response in transcription factors during development of myocardial hypertrophy. J Mol Cell Cardiol 27: 2359–2372, 1995
Zou Y, Chien KR: EFIA/YB-1 is a component of cardiac HF-1A binding activity and positively regulates transcription of the myosin light chain 2v gene. Mol Cell Biol 15: 2972–2982, 1995
Navankasattusas S, Sawadogo M, Van Bilsen M, Dang CV, Chien KR: The basic helix-loop-helix protein upstream stimulating factor regulates the cardiac ventricular myosin light chain 2 gene via independent cis regulatory elements. Mol Cell Biol 14: 7331–7339, 1994
Zhou MD, Goswami SK, Martin ME, Siddiqui MAQ: A new S serum responsive cardiac tissue specific transcription factor that recognizes the element B (MEF-2) site in myosin light chain-2 promoter. Mol Cell Biol 13: 1222–1231, 1993
Zhu H, Nguyen VT, Brown AB, Pourhosseini A, Garcia AV, Van Bilsen M, Chien KR: A novel tissue restricted zinc finger protein (HF-16) binds to the cardiac regulatory element (HF-16/MEF-2) in the rat myosin light chain 2 gene. Mol Cell Biol 13: 4432–4444, 1993
Navankasattusas S, Zhu H, Garcia AV, Evans SM, Chien KR: A ubiquitous factor (HF-1A) and a distinct muscle factor (HF-16/MEF-2) form an E-Box independent pathway for cardiac muscle gene expression. Mol Cell Biol 12: 1469–1479, 1992
Qasba P, Lin E, Zhou MD, Kumar A, Siddiqui MAQ: A single transcription factor binds to two divergent sequence elements with a common function in cardiac myosin light chain-2 promoter. Mol Cell Biol 12: 1107–1116, 1992
Shen R, Goswami SK, Mascareno E, Kumar A, Siddiqui MAQ: Tissue specific transcription of cardiac myosin light chain 2 gene is regulated by an upstream repressor element. Mol Cell Biol 11: 1676–1685, 1991
Bader D, Masaki T, Fischman DA: Immunochemical analysis of myosin heavy chain during avian myogenesis in vivo and in vitro. J Cell Biol 95: 736–770, 1982
Smeal T, Angel P, Meek J, Karin M: Different requirements for formation of Jun:Jun and Jun:Fos complexes. Genes Dev 3: 2091–2100, 1989
Angel P, Smeal T, Meek J, Karin M: Jun and v-Jun contain multiple regions that participate in transcriptional activation in an interdependent manner. New Biol 1: 35–43, 1989
Bossy-Wetzel E, Bravo R, Hanahan D: Transcription factors Jun-B and c-Jun are selectively up-regulated and functionally implicated in fibrosarcoma development. Genes Dev 6: 2340–2351, 1992
McGrew MJ, Bogdanova N, Hasegawa K, Hughes SH, Kitsis RN, Rosenthal N: distinct gene expression patterns in skeletal and cardiac muscle are dependent on common regulatory sequences in MLC1/3 locus. Mol Cell Biol 16: 4524–4534, 1996
Gorman CM, Moffat LF, Howard BM: Recombinant genomes which express chloramphenicol acetyl transferase in mammalian cells. Mol Cell Biol 2: 1044–1051, 1982
Goswami SK, Siddiqui MAQ: Molecular basis of cardiocyte cell specification. Ann NY Acad Sci 793: 259–266, 1996
Olson EN, Srivastava D: Molecular pathways controlling heart development. Science 272: 671–676, 1996
Goswami SK, Zarraga AM, Martin ME, Morgenstern D, Siddiqui MAQ: Fos-mediated repression of myosin light chain-2 gene transcription. Cell Mol Biol 38: 49–58, 1992
Kumar C, Saidepet C, Delaney P, Mendola C, Siddiqui MAQ: Expression of ventricular type myosin light chain messenger RNA in spontaneously hypertensive rat atria. Cir Res 2: 1093–1097, 1988
Harvey RP: NK-2 homeobox genes and heart development. Dev Biol 178: 203–216, 1996
Brand T, Sharma HS, Schaper W: Expression of nuclear proto-oncogenes in isoproterenol-induced cardiac hypertrophy. J Mol Cell Cardiol 25: 1325–1337, 1993
Herzig TC, Jobe SM, Aoki H, Molkentin JD, Cowley AW Jr, Izumo S, Markham BE: Angiotensin II type 1a receptor gene expression in the heart: AP-1 and GATA-4 participate in the response to pressure overload. Proc Natl Acad Sci 94: 7543–7548, 1997
Deng T, Karin M: JunB differs from c-Jun in its DNA binding and dimerization domains and represses c-Jun by formation of inactive heterodimers. Genes Dev 7: 479–490, 1993
Cahill MA, Ernst WH., Janknecht R, Nordheim A: Hypothesis: Regulatory squelching. FEBS Lett 344: 105–108, 1994
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Goswami, S.K., Shafiq, S. & Siddiqui, M. Modulation of MLC-2v gene expression by AP-1: Complex regulatory role of Jun in cardiac myocytes. Mol Cell Biochem 217, 13–20 (2001). https://doi.org/10.1023/A:1007296330181
Issue Date:
DOI: https://doi.org/10.1023/A:1007296330181