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CLP-1-Mediated Transcriptional Control of Hypertrophic Gene Programs Underlying Cardiac Hypertrophy

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Abstract

Cardiac hypertrophy is the heart’s response to increased work, pressure, or volume overload. It begins with a compensatory phase that allows the heart to meet imposed demand through rapid expression of stress response genes. A decompensatory phase follows marked by additional adaptive stress response gene expression that with prolonged stress progressively turns maladaptive, leading the heart into failure. The transition from compensatory to decompensatory hypertrophy is likely to reflect changes in the transcription factors and regulatory molecules that control these programs in response to changes in stress stimuli and the status of cardiomyocytes throughout the hypertrophic process. Our laboratory has been studying the role of one such transcriptional regulatory molecule, CLP-1 (cardiac lineage protein-1), in the cellular response to hypertrophic stimuli. CLP-1, the mouse homolog of the human HEXIM1 gene, is an inhibitor of P-TEFb (transcription elongation factor b), a component of the transcriptional apparatus that controls RNA polymerase II activity and gene transcription. Knockout of the CLP-1 gene results in a severe form of hypertrophy in fetal mice suggesting that in the absence of the CLP-1 inhibitor, uninhibited P-TEFb activity may lead to unregulated expression of stress response genes and decompensatory hypertrophy. Because of its critical role in regulating the stress gene response to hypertrophic stimuli, we review our laboratory’s work on CLP-1, its control of P-TEFb under various hypertrophic conditions, and how it may play an important role in a novel gene control mechanism, called promoter proximal pausing, that ensures the rapid expression of stress response genes in response to hypertrophic stimuli.

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References

  1. Luptak I, Balschi JA, Xing Y, et al. Decreased contractile and metabolic reserve in peroxisome proliferator-activated receptor-alpha-null hearts can be rescued by increasing glucose transport and utilization. Circulation. 2005;112:2339–46.

    Article  PubMed  CAS  Google Scholar 

  2. Ingwall JS. Energy metabolism in heart failure and remodeling. Cardiovasc Res. 2009;81:412–9.

    Article  PubMed  CAS  Google Scholar 

  3. Eghbali M, Weber KT. Collagen and the myocardium: fibrillar structure, biosynthesis and degradation in relation to hypertrophy and its regression. Mol Cell Biochem. 1990;96:1–14.

    Article  PubMed  CAS  Google Scholar 

  4. Boluyt MO, O’Neill L, Meredith AL, et al. Alterations in cardiac gene expression during the transition from stable hypertrophy to heart failure. Marked upregulation of genes encoding extracellular matrix components. Circ Res. 1994;75:23–32.

    PubMed  CAS  Google Scholar 

  5. Mujumdar VS, Tyagi SC. Temporal regulation of extracellular matrix components in transition from compensatory hypertrophy to decompensatory heart failure. J Hypertens. 1999;17:261–70.

    Article  PubMed  CAS  Google Scholar 

  6. Ho CY, Lopez B, Coelho-Filho OR, et al. Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy. N Engl J Med. 2010;363:552–63.

    Article  PubMed  CAS  Google Scholar 

  7. Dorn 2nd GW. Apoptotic and non-apoptotic programmed cardiomyocyte death in ventricular remodeling. Cardiovasc Res. 2009;81:465–73.

    Article  PubMed  CAS  Google Scholar 

  8. van Empel VP, Bertrand AT, Hofstra L, et al. Myocyte apoptosis in heart failure. Cardiovasc Res. 2005;67:21–9.

    Article  PubMed  Google Scholar 

  9. Heineke J, Molkentin JD. Regulation of cardiac hypertrophy by intracellular signaling pathways. Nat Rev Mol Cell Biol. 2006;7:589–600.

    Article  PubMed  CAS  Google Scholar 

  10. Rose BA, Force T, Wang Y. Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale. Physiol Rev. 2010;90:1507–46.

    Article  PubMed  CAS  Google Scholar 

  11. Clerk A, Cullingford TE, Fuller SJ, et al. Signaling pathways mediating cardiac myocyte gene expression in physiological and stress responses. J Cell Physiol. 2007;212:311–22.

    Article  PubMed  CAS  Google Scholar 

  12. Kehat I, Molkentin JD. Extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in cardiac hypertrophy. Ann NY Acad Sci. 2010;1188:96–102.

    Article  PubMed  CAS  Google Scholar 

  13. Black FM, Packer SE, Parker TG, et al. The vascular smooth muscle alpha-actin gene is reactivated during cardiac hypertrophy provoked by load. J Clin Invest. 1991;88:1581–8.

    Article  PubMed  CAS  Google Scholar 

  14. Bernardo BC, Weeks KL, Pretorius L, et al. Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacol Ther. 2010;128: 191–227.

    Article  PubMed  CAS  Google Scholar 

  15. Lehman JJ, Kelly DP. Gene regulatory mechanisms governing energy metabolism during cardiac hypertrophic growth. Heart Fail Rev. 2002;7:175–85.

    Article  PubMed  CAS  Google Scholar 

  16. Mann DL. Mechanisms and models in heart failure: a combinatorial approach. Circulation. 1999;100:999–1008.

    PubMed  CAS  Google Scholar 

  17. Ghatpande S, Goswami S, Mathew S, et al. Identification of a novel cardiac lineage-associated protein(cCLP-1): a candidate regulator of cardiogenesis. Dev Biol. 1999;208:210–21.

    Article  PubMed  CAS  Google Scholar 

  18. Huang F, Wagner M, Siddiqui MA. Structure, expression, and functional characterization of the mouse CLP-1 gene. Gene. 2002;292:245–59.

    Article  PubMed  CAS  Google Scholar 

  19. Rice AP. Dysregulation of positive transcription elongation factor B and myocardial hypertrophy. Circ Res. 2009;104:1327–9.

    Article  PubMed  CAS  Google Scholar 

  20. Huang F, Wagner M, Siddiqui MA. Ablation of the CLP-1 gene leads to down-regulation of the HAND1 gene and abnormality of the left ventricle of the heart and fetal death. Mech Dev. 2004;121:559–72.

    Article  PubMed  CAS  Google Scholar 

  21. Espinoza-Derout J, Wagner M, Shahmiri K, et al. Pivotal role of cardiac lineage protein-1 (CLP-1) in transcriptional elongation factor P-TEFb complex formation in cardiac hypertrophy. Cardiovasc Res. 2007;75:129–38.

    Article  PubMed  CAS  Google Scholar 

  22. Espinoza-Derout J, Wagner M, Salciccioli L, et al. Positive transcription elongation factor b activity in compensatory myocardial hypertrophy is regulated by cardiac lineage protein-1. Circ Res. 2009;104:1347–54.

    Article  PubMed  CAS  Google Scholar 

  23. Yik JH, Chen R, Nishimura R, et al. Inhibition of P-TEFb (CDK9/Cyclin T) kinase and RNA polymerase II transcription by the coordinated actions of HEXIM1 and 7SK snRNA. Mol Cell. 2003;12:971–82.

    Article  PubMed  CAS  Google Scholar 

  24. Dey A, Chao SH, Lane DP. HEXIM1 and the control of transcription elongation: from cancer and inflammation to AIDS and cardiac hypertrophy. Cell Cycle. 2007;6:1856–63.

    Article  PubMed  CAS  Google Scholar 

  25. Michels AA, Nguyen VT, Fraldi A, et al. MAQ1 and 7SK RNA interact with CDK9/cyclin T complexes in a transcription-dependent manner. Mol Cell Biol. 2003;23:4859–69.

    Article  PubMed  CAS  Google Scholar 

  26. Peterlin BM, Price DH. Controlling the elongation phase of transcription with P-TEFb. Mol Cell. 2006;23:297–305.

    Article  PubMed  CAS  Google Scholar 

  27. Price DH. Poised polymerases: on your mark…get set…go! Mol Cell. 2008;30(1):7–10.

    Article  PubMed  CAS  Google Scholar 

  28. Kohoutek J. P-TEFb- the final frontier. Cell Div. 2009;4:19.

    Article  PubMed  Google Scholar 

  29. Core LJ, Lis JT. Transcription regulation through promoter-proximal pausing of RNA polymerase II. Science. 2008;319:1791–2.

    Article  PubMed  CAS  Google Scholar 

  30. Thattaliyath BD, Livi CB, Steinhelper ME, et al. HAND1 and HAND2 are expressed in the adult-rodent heart and are modulated during cardiac hypertrophy. Biochem Biophys Res Commun. 2002;297:870–5.

    Article  PubMed  CAS  Google Scholar 

  31. Sano M, Abdellatif M, Oh H, et al. Activation and function of cyclin T-Cdk9 (positive transcription elongation factor-b) in cardiac muscle-cell hypertrophy. Nat Med. 2002;8:1310–7.

    Article  PubMed  CAS  Google Scholar 

  32. Yang Z, Zhu Q, Luo K, et al. The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription. Nature. 2001;414:317–22.

    Article  PubMed  CAS  Google Scholar 

  33. Nguyen VT, Kiss T, Michels AA, et al. 7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes. Nature. 2001;414:322–5.

    Article  PubMed  CAS  Google Scholar 

  34. Michels AA, Fraldi A, Li Q, et al. Binding of the 7SK snRNA turns the HEXIM1 protein into a P-TEFb (CDK9/cyclin T) inhibitor. EMBO J. 2004;23:2608–19.

    Article  PubMed  CAS  Google Scholar 

  35. Molkentin JD, Lu JR, Antos CL, et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell. 1998;93:215–28.

    Article  PubMed  CAS  Google Scholar 

  36. Semeniuk LM, Severson DL, Kryski AJ, Swirp SL, Molkentin JD, Duff HJ. Time-dependent systolic and diastolic function in mice overexpressing calcineurin. Am J Physiol Heart Circ Physiol. 2003;284:H425–30.

    PubMed  CAS  Google Scholar 

  37. Zeitlinger J, Stark A, Kellis M, et al. RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo. Nat Genet. 2007;39:1512–6.

    Article  PubMed  CAS  Google Scholar 

  38. Fujinaga K, Irwin D, Huang Y, et al. Dynamics of human immunodeficiency virus transcription: P-TEFb phosphorylates RD and dissociates negative effectors from the transactivation response element. Mol Cell Biol. 2004;24:787–95.

    Article  PubMed  CAS  Google Scholar 

  39. Yamada T, Yamaguchi Y, Inukai N, et al. P-TEFb-mediated phosphorylation of hSpt5 C-terminal repeats is critical for processive transcription elongation. Mol Cell. 2006;21:227–37.

    Article  PubMed  CAS  Google Scholar 

  40. Chen R, Liu M, Li H, et al. PP2B and PP1alpha cooperatively disrupt 7SK snRNP to release P-TEFb for transcription in response to Ca2+ signaling. Genes Dev. 2008;22:1356–68.

    Article  PubMed  CAS  Google Scholar 

  41. Contreras X, Barboric M, Lenasi T, et al. HMBA releases P-TEFb from HEXIM1 and 7SK snRNA via PI3K/Akt and activates HIV transcription. PLoS Pathog. 2007;3:1459–69.

    Article  PubMed  CAS  Google Scholar 

  42. Fujita T, Ryser S, Piuz I, et al. Up-regulation of P-TEFb by the MEK1-extracellular signal-regulated kinase signaling pathway contributes to stimulated transcription elongation of immediate early genes in neuroendocrine cells. Mol Cell Biol. 2008;28:1630–43.

    Article  PubMed  CAS  Google Scholar 

  43. Yamauchi-Takihara K. gp130-mediated pathway and heart failure. Future Cardiol. 2008;4(4):427–37.

    Article  PubMed  CAS  Google Scholar 

  44. Wagner M, Siddiqui MA. Signaling networks regulating cardiac myocyte survival and death. Curr Opin Investig Drugs. 2009;10:928–37.

    PubMed  CAS  Google Scholar 

  45. Beckles DL, Mascareno E, Siddiqui MA. Inhibition of Jak2 phosphorylation attenuates pressure overload cardiac hypertrophy. Vascul Pharmacol. 2006;45:350–7.

    Article  PubMed  CAS  Google Scholar 

  46. Hou T, Ray S, Brasier AR. The functional role of an interleukin 6-inducible CDK9.STAT3 complex in human gamma-fibrinogen gene expression. J Biol Chem. 2007;282:37091–102.

    Article  PubMed  CAS  Google Scholar 

  47. Zhou Q, Yik JH. The Yin and Yang of P-TEFb regulation: implications for human immunodeficiency virus gene expression and global control of cell growth and differentiation. Microbiol Mol Biol Rev. 2006;70:646–59.

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. The Center for Cardiovascular and Muscle Research and Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY, USA

    M. A. Q. Siddiqui, Michael Wagner, Jorge Espinoza-Derout, Facan Huang, Daniel Beckles & Eduardo Mascareno

Authors
  1. M. A. Q. Siddiqui
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  2. Michael Wagner
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  3. Jorge Espinoza-Derout
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  4. Facan Huang
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  5. Daniel Beckles
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  6. Eduardo Mascareno
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Corresponding author

Correspondence to M. A. Q. Siddiqui .

Editor information

Editors and Affiliations

  1. Czech Republic, Institute of Physiology, Academy of Sciences of the, Videnska 1083, Prague, 142 20, Czech Republic

    Bohuslav Ostadal

  2. Jikei University School of Medicine, Shibuya-ku, Ebisu 3-31-6, Tokyo, 150-0013, Japan

    Makoto Nagano

  3. St. Boniface General Hospital, Research Centre, Institute of Cardiovascular Sciences, Tache Avenue 351, Winnipeg, R2H 2A6, Manitoba, Canada

    Naranjan S. Dhalla

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Siddiqui, M.A.Q., Wagner, M., Espinoza-Derout, J., Huang, F., Beckles, D., Mascareno, E. (2011). CLP-1-Mediated Transcriptional Control of Hypertrophic Gene Programs Underlying Cardiac Hypertrophy. In: Ostadal, B., Nagano, M., Dhalla, N. (eds) Genes and Cardiovascular Function. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-7207-1_19

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  • DOI: https://doi.org/10.1007/978-1-4419-7207-1_19

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