Cardiac Hypertrophy - NF-AT signaling in Cardiac Hypertrophy

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NFAT signaling in cardiac hypertrophy

Cardiac hypertrophy is defined as a compensatory mechanism of the heart that helps to maintain cardiac output during pathological states. Hypertrophy leads to pathologic cardiac growth, and is associated with increased morbidity and mortality. Transcription factor NF-AT3 (NFATc4) plays a critical role in Ca(2+)/calcineurin-mediated cardiac hypertrophic signaling. NF-AT3 signaling is essential for normal cardiac valve and may be adapted specifically for transduction pathologic signals into a hypertrophic response in the heart [1], [2].

GPCRs (G-protein coupled receptors) play an important role in the regulation of cardiac function and adaptation to changes in hemodynamic burden. GPCRs involved in cardiac hypertrophy include Angiotensin II receptor, type-1 and Beta-1 adrenergic receptor activated by Angiotensin II and Noradrenaline, respectively [3], [4].

These GPCRs are coupled to three principal classes of heterotrimeric GTP-binding proteins, G-alphaS, G-alphaI and G-alphaQ/11 which transduce signals towards intracellular effectors such as enzymes and ion channels. G-proteins consist of the subunits G-alpha (G-protein alpha-s, G-protein alpha-i family and G-protein alpha-q/11) and G-beta/gamma (G-proteins beta/gamma), which upon receptor activation dissociate and independently activate signaling pathways, including activation of kinases (such as c-Src, PKC-epsilon and PKC-alpha), MAPK cascade, and increase in intracellular Ca(2+) level [5], [6], [7], [8].

Calcineurin A is a calcium/calmodulin-activated, serine-threonine phosphatase that transmits signals to the nucleus through dephosphorylation and translocation of nuclear transcription factors NFATs [9]. NF-AT3 (NF-ATc4) plays a critical role in calcineurin-mediated cardiac hypertrophic signaling [10].

In the nucleus, NF-AT3 cooperates with other transcription factors, leading to activation of transcription of genes, essential for cardiac development, and, thus, hypertrophy [11], [12], [13].

Other receptors associated with the induction of cardiac hypertrophy through the NF-AT3 pathway include IGF-1 receptor, activated by IGF-1 (Insulin Like Growth Factor-1) and gp130, which functions as a part of the cytokine receptor complex and is shared by many cytokines, including interleukin 6 (IL-6), leukemia inhibitory factor (LIF) and Cardiotrophin-1.

IGF-1 stimulates the phosphoinositide 3-kinase (PI3K)/AKT pathway, which has been shown to promote hypertrophy of cardiomyocytes [9]. Glycogen synthase kinase-3 beta (GSK3 beta) is the principal substrate of AKT(PKB) kinase [14]. The activated GSK3 beta suppresses cardiac hypertrophy, since GSK3 beta phosphorylates NFAT proteins and, thus, antagonizes action of Calcineurin A by stimulating NF-AT3 nuclear export [15], [16]. GSK3 beta also phosphorylates another transcription factor, GATA-4, and suppresses its nuclear accumulation [17]. GSK3 beta is inactivated by AKT phosphorylation that allows NF-AT3 and GATA-4 to translocate to the nucleus [18], [19].

Induction of gp130 by IL-6, LIF and Cardiotrophyn-1 leads to activation of MAPK pathway [20], [21], [22].

Cardiotrophin-1 and LIF-induced activation of gp130 transduces hypertrophic signal through interaction of scaffolding/docking protein GAB1 with tyrosine phosphatase SHP-2 in cardiomyocytes. GAB1/SHP-2 signaling regulates activation of MEK5/ERK5 MAP kinases, leading to gp130-dependent elongation of cardiomyocytes [23], [24], [25].

ERK5 phosphorylates and activates transcription factors of the myocyte enhancer factor 2 (MEF2) family (MEF2A, MEF2C, MEF2D) that nave been implicated as a signal-responsive mediators of the cardiac transcriptional program [26], [27], [28].

Class II histone deacetylases (HDAC4, HDAC5, HDAC7 and HDAC9) have been shown to interact with MEF2s and play an important role in the repression of cardiac hypertrophy. Class II HDAC activity is inhibited by calcineurin and through phosphorylation by Ca2+/calmodulin-dependent kinase (CaMKIV) [29], [30], [31], [32]. Protein kinase PKC-mu, a downstream effector of PKC-epsilon, directly phosphorylates HDAC5 and, possibly, HDAC7, and stimulates their export from the nucleus [3], [33], [34].

The calmodulin binding transcription activator 2 (CAMTA2) is shown to be an indispensable transcription coactivator for cardiac hypertrophy. CAMTA2 is activated by the dissociation of HDAC5 and promotes transcription of genes through its interaction with Nkx2-5 [35], [36].

Transcription factors and co-factors (GATA-4, NKX-2.5, CAMTA2, MEF2, HAND1, HAND2, CBP and p300) cooperate with NF-AT3 to express genes, involved in cardiac hypertrophy, including alpha- and beta-myosin (alpha-MHC and beta-MHC); Troponin I, cardiac; Troponin T, cardiac; Sodium/calcium exchanger NCX1; Endothelin-1; Actin, alpha cardiac (ACTC); Adenylosuccinate synthetase (ADSSL1); and Atrial natriuretic factor (ANP) [11], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48].

References:

  1. Olson EN, Molkentin JD
    Prevention of cardiac hypertrophy by calcineurin inhibition: hope or hype? Circulation research 1999 Apr 2;84(6):623-32
  2. Molkentin JD
    Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. Cardiovascular research 2004 Aug 15;63(3):467-75
  3. Iwata M, Maturana A, Hoshijima M, Tatematsu K, Okajima T, Vandenheede JR, Van Lint J, Tanizawa K, Kuroda S
    PKCepsilon-PKD1 signaling complex at Z-discs plays a pivotal role in the cardiac hypertrophy induced by G-protein coupling receptor agonists. Biochemical and biophysical research communications 2005 Feb 25;327(4):1105-13
  4. Liggett SB
    Cardiac 7-transmembrane-spanning domain receptor portfolios: diversify, diversify, diversify. The Journal of clinical investigation 2006 Apr;116(4):875-7
  5. Zhang L, Li L, Wu LL
    [Alterations of G proteins in heart diseases]. Sheng li ke xue jin zhan [Progress in physiology] 2003 Jan;34(1):32-6
  6. Bai H, Wu LL, Xing DQ, Liu J, Zhao YL
    Angiotensin II induced upregulation of G alpha q/11, phospholipase C beta 3 and extracellular signal-regulated kinase 1/2 via angiotensin II type 1 receptor. Chinese medical journal 2004 Jan;117(1):88-93
  7. Levy BI
    How to explain the differences between renin angiotensin system modulators. American journal of hypertension 2005 Sep;18(9 Pt 2):134S-141S
  8. Wettschureck N, Offermanns S
    Mammalian G proteins and their cell type specific functions. Physiological reviews 2005 Oct;85(4):1159-204
  9. Wilkins BJ, Dai YS, Bueno OF, Parsons SA, Xu J, Plank DM, Jones F, Kimball TR, Molkentin JD
    Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circulation research 2004 Jan 9;94(1):110-8
  10. Sugden PH
    Signaling in myocardial hypertrophy: life after calcineurin? Circulation research 1999 Apr 2;84(6):633-46
  11. Morkin E
    Control of cardiac myosin heavy chain gene expression. Microscopy research and technique 2000 Sep 15;50(6):522-31
  12. Pu WT, Ma Q, Izumo S
    NFAT transcription factors are critical survival factors that inhibit cardiomyocyte apoptosis during phenylephrine stimulation in vitro. Circulation research 2003 Apr 18;92(7):725-31
  13. Akazawa H, Komuro I
    Roles of cardiac transcription factors in cardiac hypertrophy. Circulation research 2003 May 30;92(10):1079-88
  14. Condorelli G, Drusco A, Stassi G, Bellacosa A, Roncarati R, Iaccarino G, Russo MA, Gu Y, Dalton N, Chung C, Latronico MV, Napoli C, Sadoshima J, Croce CM, Ross J Jr
    Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proceedings of the National Academy of Sciences of the United States of America 2002 Sep 17;99(19):12333-8
  15. Antos CL, McKinsey TA, Frey N, Kutschke W, McAnally J, Shelton JM, Richardson JA, Hill JA, Olson EN
    Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivo. Proceedings of the National Academy of Sciences of the United States of America 2002 Jan 22;99(2):907-12
  16. Vyas DR, Spangenburg EE, Abraha TW, Childs TE, Booth FW
    GSK-3beta negatively regulates skeletal myotube hypertrophy. American journal of physiology. Cell physiology 2002 Aug;283(2):C545-51
  17. Morisco C, Seta K, Hardt SE, Lee Y, Vatner SF, Sadoshima J
    Glycogen synthase kinase 3beta regulates GATA4 in cardiac myocytes. The Journal of biological chemistry 2001 Jul 27;276(30):28586-97
  18. Brazil DP, Hemmings BA
    Ten years of protein kinase B signalling: a hard Akt to follow. Trends in biochemical sciences 2001 Nov;26(11):657-64
  19. Seimi SK, Seinosuke K, Tsuyoshi S, Tomomi U, Tetsuaki H, Miki K, Ryuji T, Kenji I, Mitsuhiro Y
    Glycogen synthase kinase-3beta is involved in the process of myocardial hypertrophy stimulated by insulin-like growth factor-1. Circulation journal : official journal of the Japanese Circulation Society 2004 Mar;68(3):247-53
  20. Murata M, Fukuda K, Ishida H, Miyoshi S, Koura T, Kodama H, Nakazawa HK, Ogawa S
    Leukemia inhibitory factor, a potent cardiac hypertrophic cytokine, enhances L-type Ca2+ current and [Ca2+]i transient in cardiomyocytes. Journal of molecular and cellular cardiology 1999 Jan;31(1):237-45
  21. Kodama H, Fukuda K, Pan J, Sano M, Takahashi T, Kato T, Makino S, Manabe T, Murata M, Ogawa S
    Significance of ERK cascade compared with JAK/STAT and PI3-K pathway in gp130-mediated cardiac hypertrophy. American journal of physiology. Heart and circulatory physiology 2000 Oct;279(4):H1635-44
  22. Booz GW, Day JN, Speth R, Baker KM
    Cytokine G-protein signaling crosstalk in cardiomyocytes: attenuation of Jak-STAT activation by endothelin-1. Molecular and cellular biochemistry 2002 Nov;240(1-2):39-46
  23. Nakaoka Y, Nishida K, Fujio Y, Izumi M, Terai K, Oshima Y, Sugiyama S, Matsuda S, Koyasu S, Yamauchi-Takihara K, Hirano T, Kawase I, Hirota H
    Activation of gp130 transduces hypertrophic signal through interaction of scaffolding/docking protein Gab1 with tyrosine phosphatase SHP2 in cardiomyocytes. Circulation research 2003 Aug 8;93(3):221-9
  24. Wang Y
    Fill a Gab(1) in cardiac hypertrophy signaling: search a missing link between gp130 and ERK5 in hypertrophic remodeling in heart. Circulation research 2003 Aug 8;93(3):186-8
  25. Takahashi N, Saito Y, Kuwahara K, Harada M, Tanimoto K, Nakagawa Y, Kawakami R, Nakanishi M, Yasuno S, Usami S, Yoshimura A, Nakao K
    Hypertrophic responses to cardiotrophin-1 are not mediated by STAT3, but via a MEK5-ERK5 pathway in cultured cardiomyocytes. Journal of molecular and cellular cardiology 2005 Jan;38(1):185-92
  26. Kasler HG, Victoria J, Duramad O, Winoto A
    ERK5 is a novel type of mitogen-activated protein kinase containing a transcriptional activation domain. Molecular and cellular biology 2000 Nov;20(22):8382-9
  27. Nadruz W Jr, Kobarg CB, Constancio SS, Corat PD, Franchini KG
    Load-induced transcriptional activation of c-jun in rat myocardium: regulation by myocyte enhancer factor 2. Circulation research 2003 Feb 7;92(2):243-51
  28. Xu J, Gong NL, Bodi I, Aronow BJ, Backx PH, Molkentin JD
    Myocyte enhancer factors 2A and 2C induce dilated cardiomyopathy in transgenic mice. The Journal of biological chemistry 2006 Apr 7;281(14):9152-62
  29. Grégoire S, Tremblay AM, Xiao L, Yang Q, Ma K, Nie J, Mao Z, Wu Z, Giguère V, Yang XJ
    Control of MEF2 transcriptional activity by coordinated phosphorylation and sumoylation. The Journal of biological chemistry 2006 Feb 17;281(7):4423-33
  30. Backs J, Olson EN
    Control of cardiac growth by histone acetylation/deacetylation. Circulation research 2006 Jan 6;98(1):15-24
  31. Olson EN, Backs J, McKinsey TA
    Control of cardiac hypertrophy and heart failure by histone acetylation/deacetylation. Novartis Foundation symposium 2006;274:3-12; discussion 13-9, 152-5, 272-6
  32. Karamboulas C, Swedani A, Ward C, Al-Madhoun AS, Wilton S, Boisvenue S, Ridgeway AG, Skerjanc IS
    HDAC activity regulates entry of mesoderm cells into the cardiac muscle lineage. Journal of cell science 2006 Oct 15;119(Pt 20):4305-14
  33. Vega RB, Harrison BC, Meadows E, Roberts CR, Papst PJ, Olson EN, McKinsey TA
    Protein kinases C and D mediate agonist-dependent cardiac hypertrophy through nuclear export of histone deacetylase 5. Molecular and cellular biology 2004 Oct;24(19):8374-85
  34. Parra M, Kasler H, McKinsey TA, Olson EN, Verdin E
    Protein kinase D1 phosphorylates HDAC7 and induces its nuclear export after T-cell receptor activation. The Journal of biological chemistry 2005 Apr 8;280(14):13762-70
  35. Schwartz RJ, Schneider MD
    CAMTA in cardiac hypertrophy. Cell 2006 May 5;125(3):427-9
  36. Song K, Backs J, McAnally J, Qi X, Gerard RD, Richardson JA, Hill JA, Bassel-Duby R, Olson EN
    The transcriptional coactivator CAMTA2 stimulates cardiac growth by opposing class II histone deacetylases. Cell 2006 May 5;125(3):453-66
  37. Sartorelli V, Huang J, Hamamori Y, Kedes L
    Molecular mechanisms of myogenic coactivation by p300: direct interaction with the activation domain of MyoD and with the MADS box of MEF2C. Molecular and cellular biology 1997 Feb;17(2):1010-26
  38. Lewis AL, Xia Y, Datta SK, McMillin J, Kellems RE
    Combinatorial interactions regulate cardiac expression of the murine adenylosuccinate synthetase 1 gene. The Journal of biological chemistry 1999 May 14;274(20):14188-97
  39. Xia Y, McMillin JB, Lewis A, Moore M, Zhu WG, Williams RS, Kellems RE
    Electrical stimulation of neonatal cardiac myocytes activates the NFAT3 and GATA4 pathways and up-regulates the adenylosuccinate synthetase 1 gene. The Journal of biological chemistry 2000 Jan 21;275(3):1855-63
  40. Bhavsar PK, Dellow KA, Yacoub MH, Brand NJ, Barton PJ
    Identification of cis-acting DNA elements required for expression of the human cardiac troponin I gene promoter. Journal of molecular and cellular cardiology 2000 Jan;32(1):95-108
  41. Morimoto T, Hasegawa K, Wada H, Kakita T, Kaburagi S, Yanazume T, Sasayama S
    Calcineurin-GATA4 pathway is involved in beta-adrenergic agonist-responsive endothelin-1 transcription in cardiac myocytes. The Journal of biological chemistry 2001 Sep 14;276(37):34983-9
  42. Jamali M, Rogerson PJ, Wilton S, Skerjanc IS
    Nkx2-5 activity is essential for cardiomyogenesis. The Journal of biological chemistry 2001 Nov 9;276(45):42252-8
  43. Wen HY, Xia Y, Young ME, Taegtmeyer H, Kellems RE
    The adenylosuccinate synthetase-1 gene is activated in the hypertrophied heart. Journal of cellular and molecular medicine 2002 Apr-Jun;6(2):235-43
  44. Schubert W, Yang XY, Yang TT, Factor SM, Lisanti MP, Molkentin JD, Rincon M, Chow CW
    Requirement of transcription factor NFAT in developing atrial myocardium. The Journal of cell biology 2003 Jun 9;161(5):861-74
  45. Zang MX, Li Y, Xue LX, Jia HT, Jing H
    Cooperative activation of atrial naturetic peptide promoter by dHAND and MEF2C. Journal of cellular biochemistry 2004 Dec 15;93(6):1255-66
  46. Ma K, Chan JK, Zhu G, Wu Z
    Myocyte enhancer factor 2 acetylation by p300 enhances its DNA binding activity, transcriptional activity, and myogenic differentiation. Molecular and cellular biology 2005 May;25(9):3575-82
  47. Morin S, Pozzulo G, Robitaille L, Cross J, Nemer M
    MEF2-dependent recruitment of the HAND1 transcription factor results in synergistic activation of target promoters. The Journal of biological chemistry 2005 Sep 16;280(37):32272-8
  48. Xu L, Renaud L, Müller JG, Baicu CF, Bonnema DD, Zhou H, Kappler CS, Kubalak SW, Zile MR, Conway SJ, Menick DR
    Regulation of Ncx1 expression. Identification of regulatory elements mediating cardiac-specific expression and up-regulation. The Journal of biological chemistry 2006 Nov 10;281(45):34430-40

  1. Olson EN, Molkentin JD
    Prevention of cardiac hypertrophy by calcineurin inhibition: hope or hype? Circulation research 1999 Apr 2;84(6):623-32
  2. Molkentin JD
    Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. Cardiovascular research 2004 Aug 15;63(3):467-75
  3. Iwata M, Maturana A, Hoshijima M, Tatematsu K, Okajima T, Vandenheede JR, Van Lint J, Tanizawa K, Kuroda S
    PKCepsilon-PKD1 signaling complex at Z-discs plays a pivotal role in the cardiac hypertrophy induced by G-protein coupling receptor agonists. Biochemical and biophysical research communications 2005 Feb 25;327(4):1105-13
  4. Liggett SB
    Cardiac 7-transmembrane-spanning domain receptor portfolios: diversify, diversify, diversify. The Journal of clinical investigation 2006 Apr;116(4):875-7
  5. Zhang L, Li L, Wu LL
    [Alterations of G proteins in heart diseases]. Sheng li ke xue jin zhan [Progress in physiology] 2003 Jan;34(1):32-6
  6. Bai H, Wu LL, Xing DQ, Liu J, Zhao YL
    Angiotensin II induced upregulation of G alpha q/11, phospholipase C beta 3 and extracellular signal-regulated kinase 1/2 via angiotensin II type 1 receptor. Chinese medical journal 2004 Jan;117(1):88-93
  7. Levy BI
    How to explain the differences between renin angiotensin system modulators. American journal of hypertension 2005 Sep;18(9 Pt 2):134S-141S
  8. Wettschureck N, Offermanns S
    Mammalian G proteins and their cell type specific functions. Physiological reviews 2005 Oct;85(4):1159-204
  9. Wilkins BJ, Dai YS, Bueno OF, Parsons SA, Xu J, Plank DM, Jones F, Kimball TR, Molkentin JD
    Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circulation research 2004 Jan 9;94(1):110-8
  10. Sugden PH
    Signaling in myocardial hypertrophy: life after calcineurin? Circulation research 1999 Apr 2;84(6):633-46
  11. Morkin E
    Control of cardiac myosin heavy chain gene expression. Microscopy research and technique 2000 Sep 15;50(6):522-31
  12. Pu WT, Ma Q, Izumo S
    NFAT transcription factors are critical survival factors that inhibit cardiomyocyte apoptosis during phenylephrine stimulation in vitro. Circulation research 2003 Apr 18;92(7):725-31
  13. Akazawa H, Komuro I
    Roles of cardiac transcription factors in cardiac hypertrophy. Circulation research 2003 May 30;92(10):1079-88
  14. Condorelli G, Drusco A, Stassi G, Bellacosa A, Roncarati R, Iaccarino G, Russo MA, Gu Y, Dalton N, Chung C, Latronico MV, Napoli C, Sadoshima J, Croce CM, Ross J Jr
    Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proceedings of the National Academy of Sciences of the United States of America 2002 Sep 17;99(19):12333-8
  15. Antos CL, McKinsey TA, Frey N, Kutschke W, McAnally J, Shelton JM, Richardson JA, Hill JA, Olson EN
    Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivo. Proceedings of the National Academy of Sciences of the United States of America 2002 Jan 22;99(2):907-12
  16. Vyas DR, Spangenburg EE, Abraha TW, Childs TE, Booth FW
    GSK-3beta negatively regulates skeletal myotube hypertrophy. American journal of physiology. Cell physiology 2002 Aug;283(2):C545-51
  17. Morisco C, Seta K, Hardt SE, Lee Y, Vatner SF, Sadoshima J
    Glycogen synthase kinase 3beta regulates GATA4 in cardiac myocytes. The Journal of biological chemistry 2001 Jul 27;276(30):28586-97
  18. Brazil DP, Hemmings BA
    Ten years of protein kinase B signalling: a hard Akt to follow. Trends in biochemical sciences 2001 Nov;26(11):657-64
  19. Seimi SK, Seinosuke K, Tsuyoshi S, Tomomi U, Tetsuaki H, Miki K, Ryuji T, Kenji I, Mitsuhiro Y
    Glycogen synthase kinase-3beta is involved in the process of myocardial hypertrophy stimulated by insulin-like growth factor-1. Circulation journal : official journal of the Japanese Circulation Society 2004 Mar;68(3):247-53
  20. Murata M, Fukuda K, Ishida H, Miyoshi S, Koura T, Kodama H, Nakazawa HK, Ogawa S
    Leukemia inhibitory factor, a potent cardiac hypertrophic cytokine, enhances L-type Ca2+ current and [Ca2+]i transient in cardiomyocytes. Journal of molecular and cellular cardiology 1999 Jan;31(1):237-45
  21. Kodama H, Fukuda K, Pan J, Sano M, Takahashi T, Kato T, Makino S, Manabe T, Murata M, Ogawa S
    Significance of ERK cascade compared with JAK/STAT and PI3-K pathway in gp130-mediated cardiac hypertrophy. American journal of physiology. Heart and circulatory physiology 2000 Oct;279(4):H1635-44
  22. Booz GW, Day JN, Speth R, Baker KM
    Cytokine G-protein signaling crosstalk in cardiomyocytes: attenuation of Jak-STAT activation by endothelin-1. Molecular and cellular biochemistry 2002 Nov;240(1-2):39-46
  23. Nakaoka Y, Nishida K, Fujio Y, Izumi M, Terai K, Oshima Y, Sugiyama S, Matsuda S, Koyasu S, Yamauchi-Takihara K, Hirano T, Kawase I, Hirota H
    Activation of gp130 transduces hypertrophic signal through interaction of scaffolding/docking protein Gab1 with tyrosine phosphatase SHP2 in cardiomyocytes. Circulation research 2003 Aug 8;93(3):221-9
  24. Wang Y
    Fill a Gab(1) in cardiac hypertrophy signaling: search a missing link between gp130 and ERK5 in hypertrophic remodeling in heart. Circulation research 2003 Aug 8;93(3):186-8
  25. Takahashi N, Saito Y, Kuwahara K, Harada M, Tanimoto K, Nakagawa Y, Kawakami R, Nakanishi M, Yasuno S, Usami S, Yoshimura A, Nakao K
    Hypertrophic responses to cardiotrophin-1 are not mediated by STAT3, but via a MEK5-ERK5 pathway in cultured cardiomyocytes. Journal of molecular and cellular cardiology 2005 Jan;38(1):185-92
  26. Kasler HG, Victoria J, Duramad O, Winoto A
    ERK5 is a novel type of mitogen-activated protein kinase containing a transcriptional activation domain. Molecular and cellular biology 2000 Nov;20(22):8382-9
  27. Nadruz W Jr, Kobarg CB, Constancio SS, Corat PD, Franchini KG
    Load-induced transcriptional activation of c-jun in rat myocardium: regulation by myocyte enhancer factor 2. Circulation research 2003 Feb 7;92(2):243-51
  28. Xu J, Gong NL, Bodi I, Aronow BJ, Backx PH, Molkentin JD
    Myocyte enhancer factors 2A and 2C induce dilated cardiomyopathy in transgenic mice. The Journal of biological chemistry 2006 Apr 7;281(14):9152-62
  29. Grégoire S, Tremblay AM, Xiao L, Yang Q, Ma K, Nie J, Mao Z, Wu Z, Giguère V, Yang XJ
    Control of MEF2 transcriptional activity by coordinated phosphorylation and sumoylation. The Journal of biological chemistry 2006 Feb 17;281(7):4423-33
  30. Backs J, Olson EN
    Control of cardiac growth by histone acetylation/deacetylation. Circulation research 2006 Jan 6;98(1):15-24
  31. Olson EN, Backs J, McKinsey TA
    Control of cardiac hypertrophy and heart failure by histone acetylation/deacetylation. Novartis Foundation symposium 2006;274:3-12; discussion 13-9, 152-5, 272-6
  32. Karamboulas C, Swedani A, Ward C, Al-Madhoun AS, Wilton S, Boisvenue S, Ridgeway AG, Skerjanc IS
    HDAC activity regulates entry of mesoderm cells into the cardiac muscle lineage. Journal of cell science 2006 Oct 15;119(Pt 20):4305-14
  33. Vega RB, Harrison BC, Meadows E, Roberts CR, Papst PJ, Olson EN, McKinsey TA
    Protein kinases C and D mediate agonist-dependent cardiac hypertrophy through nuclear export of histone deacetylase 5. Molecular and cellular biology 2004 Oct;24(19):8374-85
  34. Parra M, Kasler H, McKinsey TA, Olson EN, Verdin E
    Protein kinase D1 phosphorylates HDAC7 and induces its nuclear export after T-cell receptor activation. The Journal of biological chemistry 2005 Apr 8;280(14):13762-70
  35. Schwartz RJ, Schneider MD
    CAMTA in cardiac hypertrophy. Cell 2006 May 5;125(3):427-9
  36. Song K, Backs J, McAnally J, Qi X, Gerard RD, Richardson JA, Hill JA, Bassel-Duby R, Olson EN
    The transcriptional coactivator CAMTA2 stimulates cardiac growth by opposing class II histone deacetylases. Cell 2006 May 5;125(3):453-66
  37. Sartorelli V, Huang J, Hamamori Y, Kedes L
    Molecular mechanisms of myogenic coactivation by p300: direct interaction with the activation domain of MyoD and with the MADS box of MEF2C. Molecular and cellular biology 1997 Feb;17(2):1010-26
  38. Lewis AL, Xia Y, Datta SK, McMillin J, Kellems RE
    Combinatorial interactions regulate cardiac expression of the murine adenylosuccinate synthetase 1 gene. The Journal of biological chemistry 1999 May 14;274(20):14188-97
  39. Xia Y, McMillin JB, Lewis A, Moore M, Zhu WG, Williams RS, Kellems RE
    Electrical stimulation of neonatal cardiac myocytes activates the NFAT3 and GATA4 pathways and up-regulates the adenylosuccinate synthetase 1 gene. The Journal of biological chemistry 2000 Jan 21;275(3):1855-63
  40. Bhavsar PK, Dellow KA, Yacoub MH, Brand NJ, Barton PJ
    Identification of cis-acting DNA elements required for expression of the human cardiac troponin I gene promoter. Journal of molecular and cellular cardiology 2000 Jan;32(1):95-108
  41. Morimoto T, Hasegawa K, Wada H, Kakita T, Kaburagi S, Yanazume T, Sasayama S
    Calcineurin-GATA4 pathway is involved in beta-adrenergic agonist-responsive endothelin-1 transcription in cardiac myocytes. The Journal of biological chemistry 2001 Sep 14;276(37):34983-9
  42. Jamali M, Rogerson PJ, Wilton S, Skerjanc IS
    Nkx2-5 activity is essential for cardiomyogenesis. The Journal of biological chemistry 2001 Nov 9;276(45):42252-8
  43. Wen HY, Xia Y, Young ME, Taegtmeyer H, Kellems RE
    The adenylosuccinate synthetase-1 gene is activated in the hypertrophied heart. Journal of cellular and molecular medicine 2002 Apr-Jun;6(2):235-43
  44. Schubert W, Yang XY, Yang TT, Factor SM, Lisanti MP, Molkentin JD, Rincon M, Chow CW
    Requirement of transcription factor NFAT in developing atrial myocardium. The Journal of cell biology 2003 Jun 9;161(5):861-74
  45. Zang MX, Li Y, Xue LX, Jia HT, Jing H
    Cooperative activation of atrial naturetic peptide promoter by dHAND and MEF2C. Journal of cellular biochemistry 2004 Dec 15;93(6):1255-66
  46. Ma K, Chan JK, Zhu G, Wu Z
    Myocyte enhancer factor 2 acetylation by p300 enhances its DNA binding activity, transcriptional activity, and myogenic differentiation. Molecular and cellular biology 2005 May;25(9):3575-82
  47. Morin S, Pozzulo G, Robitaille L, Cross J, Nemer M
    MEF2-dependent recruitment of the HAND1 transcription factor results in synergistic activation of target promoters. The Journal of biological chemistry 2005 Sep 16;280(37):32272-8
  48. Xu L, Renaud L, Müller JG, Baicu CF, Bonnema DD, Zhou H, Kappler CS, Kubalak SW, Zile MR, Conway SJ, Menick DR
    Regulation of Ncx1 expression. Identification of regulatory elements mediating cardiac-specific expression and up-regulation. The Journal of biological chemistry 2006 Nov 10;281(45):34430-40

Target Details

Click on a target from the pathway image to view related information.