Shuttling of HDAC5 in H9C2 cells regulates YY1 function through CaMKIV/PKD and PP2A.

YY1 is a transcription factor that can activate or repress transcription of a variety of genes and is involved in several developmental processes. YY1 is a repressor of transcription in differentiated H9C2 cells and in neonatal cardiac myocytes but an activator of transcription in undifferentiated H9C2 cells. We now present a detailed analysis of the functional domains of YY1 when it is acting as a repressor or an activator and identify the mechanism whereby its function is regulated in the differentiation of H9C2 cells. We show that histone deacetylase 5 (HDAC5) is localized to the cytoplasm in undifferentiated H9C2 cells and that this localization is dependent on Ca(2+)/calmodulin-dependent kinase IV (CaMKIV) and/or protein kinase D (PKD). In differentiated cells, HDAC5 is nuclear and interacts with YY1. Finally, we show that HDAC5 localization in differentiated cells is dependent on phosphatase 2A (PP2A). Our results suggest that a signaling mechanism that involves CaMKIV/PKD and PP2A controls YY1 function through regulation of HDAC5 and is important in the maintenance of muscle differentiation.

[1]  P. Karczewski,et al.  Regulation of the human atrial myosin light chain 1 promoter by Ca2+‐calmodulin‐dependent signaling pathways , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[2]  Yewei Liu,et al.  Activity-dependent and -independent nuclear fluxes of HDAC4 mediated by different kinases in adult skeletal muscle , 2005, The Journal of cell biology.

[3]  C. Long,et al.  Yin Yang 1 represses α-myosin heavy chain gene expression in pathologic cardiac hypertrophy , 2004 .

[4]  B. Harrison,et al.  The CRM1 Nuclear Export Receptor Controls Pathological Cardiac Gene Expression , 2004, Molecular and Cellular Biology.

[5]  L. Leinwand,et al.  The Ku Protein Complex Interacts with YY1, Is Up-Regulated in Human Heart Failure, and Represses α Myosin Heavy-Chain Gene Expression , 2004, Molecular and Cellular Biology.

[6]  Rick B. Vega,et al.  Protein Kinases C and D Mediate Agonist-Dependent Cardiac Hypertrophy through Nuclear Export of Histone Deacetylase 5 , 2004, Molecular and Cellular Biology.

[7]  Stuart S Levine,et al.  Division of labor in polycomb group repression. , 2004, Trends in biochemical sciences.

[8]  G. Breithardt,et al.  Ventricular arrhythmias, increased cardiac calmodulin kinase II expression, and altered repolarization kinetics in ANP receptor deficient mice. , 2004, Journal of molecular and cellular cardiology.

[9]  S. R. Grant,et al.  CaM kinase IIδC phosphorylation of 14-3-3β in vascular smooth muscle cells: Activation of class II HDAC repression , 2004, Molecular and Cellular Biochemistry.

[10]  M. K. Meintzer,et al.  Inactivation of the Myocyte Enhancer Factor-2 Repressor Histone Deacetylase-5 by Endogenous Ca2//Calmodulin-dependent Kinase II Promotes Depolarization-mediated Cerebellar Granule Neuron Survival* , 2003, Journal of Biological Chemistry.

[11]  C. Long,et al.  Yin Yang 1 Is Increased in Human Heart Failure and Represses the Activity of the Human α-Myosin Heavy Chain Promoter* , 2003, Journal of Biological Chemistry.

[12]  N. Bonini,et al.  Transcription factor YY1 functions as a PcG protein in vivo , 2003, The EMBO journal.

[13]  Chun Li Zhang,et al.  Signaling chromatin to make muscle. , 2002, Current opinion in cell biology.

[14]  T. Kondo,et al.  Overexpression of Calreticulin Modulates Protein Kinase B/Akt Signaling to Promote Apoptosis during Cardiac Differentiation of Cardiomyoblast H9c2 Cells* , 2002, The Journal of Biological Chemistry.

[15]  K. Malik,et al.  Functional Significance of Activation of Calcium/Calmodulin–Dependent Protein Kinase II in Angiotensin II–Induced Vascular Hyperplasia and Hypertension , 2002, Hypertension.

[16]  Tong Zhang,et al.  The Cardiac-specific Nuclear δB Isoform of Ca2+/Calmodulin-dependent Protein Kinase II Induces Hypertrophy and Dilated Cardiomyopathy Associated with Increased Protein Phosphatase 2A Activity* , 2002, The Journal of Biological Chemistry.

[17]  E. Olson,et al.  MEF2: a calcium-dependent regulator of cell division, differentiation and death. , 2002, Trends in biochemical sciences.

[18]  L. Kedes,et al.  Class I histone deacetylases sequentially interact with MyoD and pRb during skeletal myogenesis. , 2001, Molecular cell.

[19]  E. Olson,et al.  Identification of a Signal-Responsive Nuclear Export Sequence in Class II Histone Deacetylases , 2001, Molecular and Cellular Biology.

[20]  Ya-Li Yao,et al.  Regulation of Transcription Factor YY1 by Acetylation and Deacetylation , 2001, Molecular and Cellular Biology.

[21]  E. Miska,et al.  Differential localization of HDAC4 orchestrates muscle differentiation. , 2001, Nucleic acids research.

[22]  S. Bhalla,et al.  Cooperative Activation by GATA-4 and YY1 of the Cardiac B-type Natriuretic Peptide Promoter* , 2001, The Journal of Biological Chemistry.

[23]  E. Olson,et al.  Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation , 2000, Nature.

[24]  C. Long,et al.  IL-1 β Increases Abundance and Activity of the Negative Transcriptional Regulator Yin Yang-1 (YY1) in Neonatal Rat Cardiac Myocytes ☆ , 2000 .

[25]  T. Lankisch,et al.  A possible role for Ca(2+)/calmodulin-dependent protein kinase IV during pancreatic acinar stimulus-secretion coupling. , 2000, Biochimica et biophysica acta.

[26]  E. Olson,et al.  Signal-dependent activation of the MEF2 transcription factor by dissociation from histone deacetylases. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[27]  P. Lory,et al.  Modulation of L-type Calcium Channel Expression during Retinoic Acid-induced Differentiation of H9C2 Cardiac Cells* , 1999, The Journal of Biological Chemistry.

[28]  E. Seto,et al.  Unlocking the mechanisms of transcription factor YY1: are chromatin modifying enzymes the key? , 1999, Gene.

[29]  A. Marotta,et al.  Identification of Kinase-Phosphatase Signaling Modules Composed of p70 S6 Kinase-Protein Phosphatase 2A (PP2A) and p21-activated Kinase-PP2A* , 1999, The Journal of Biological Chemistry.

[30]  M. Atchison,et al.  Identification of YY1 sequences necessary for association with the nuclear matrix and for transcriptional repression functions , 1998, Journal of cellular biochemistry.

[31]  P. Karczewski,et al.  Differentiation‐dependent expression of cardiac δ‐CaMKII isoforms , 1998 .

[32]  P. Karczewski,et al.  Differentiation-dependent expression of cardiac delta-CaMKII isoforms. , 1998, Journal of cellular biochemistry.

[33]  R. Schwartz,et al.  Competition between negative acting YY1 versus positive acting serum response factor and tinman homologue Nkx-2.5 regulates cardiac alpha-actin promoter activity. , 1997, Molecular endocrinology.

[34]  M. Atchison,et al.  Characterization of Functional Domains within the Multifunctional Transcription Factor, YY1 (*) , 1995, The Journal of Biological Chemistry.

[35]  A. Ishida,et al.  A novel highly specific and potent inhibitor of calmodulin-dependent protein kinase II. , 1995, Biochemical and biophysical research communications.

[36]  E. Moran,et al.  Relief of YY1 transcriptional repression by adenovirus E1A is mediated by E1A-associated protein p300. , 1995, Genes & development.

[37]  J. Wang,et al.  Functional interactions between YY1 and adenovirus E1A. , 1995, Nucleic acids research.

[38]  E. Seto,et al.  Adenovirus E1A proteins interact with the cellular YY1 transcription factor , 1995, Journal of virology.

[39]  S. Hanks,et al.  Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases , 1995, Molecular and cellular biology.

[40]  T. Lee,et al.  Displacement of BrdUrd-induced YY1 by serum response factor activates skeletal alpha-actin transcription in embryonic myoblasts. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[41]  P. Simpson,et al.  The cardiac beta-myosin heavy chain isogene is induced selectively in alpha 1-adrenergic receptor-stimulated hypertrophy of cultured rat heart myocytes. , 1990, The Journal of clinical investigation.