Positive transcription elongation factor b activity in compensatory myocardial hypertrophy is regulated by cardiac lineage protein-1.
Emerging evidence illustrates the importance of the positive transcription elongation factor (P-TEF)b in control of global RNA synthesis, which constitutes a major feature of the compensatory response to diverse hypertrophic stimuli in cardiomyocytes. P-TEFb complex, composed of cyclin T and cdk9, is critical for elongation of nascent RNA chains via phosphorylation of the carboxyl-terminal domain of RNA polymerase (Pol) II. We and others have shown that the activity of P-TEFb is inhibited by its association with cardiac lineage protein (CLP)-1, the mouse homolog of human HEXIM1, in various physiological and pathological conditions. To investigate the mechanism of control of P-TEFb activity by CLP-1 in cardiac hypertrophy, we used a transgenic mouse model of hypertrophy caused by overexpression of calcineurin in the heart. We observed that the level of CLP-1 associated with P-TEFb was reduced markedly in hypertrophic hearts. We also generated bigenic mice (MHC-cyclin T1/CLP-1(+/-)) by crossing MHC-cyclin T1 transgenic mice with CLP-1 heterozygote. The bigenic mice exhibit enhanced susceptibility to hypertrophy that is accompanied with an increase in cdk9 activity via an increase in serine 2 phosphorylation of carboxyl-terminal domain and an increase in GLUT1/GLUT4 ratio. These mice have compensated systolic function without evidence of fibrosis and reduced lifespan. These data suggest that the reduced level of CLP-1 introduced in the background of elevated levels of cyclin T1 elevates derepression of P-TEFb activity and emphasizes the importance of the role of CLP-1 in the mechanism governing compensatory hypertrophy in cardiomyocytes.
Espinoza-Derout
Jorge
J
Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, 450 Clarkson Ave, Brooklyn, NY 11203, USA.
Wagner
Michael
M
Salciccioli
Louis
L
Lazar
Jason M
JM
Bhaduri
Sikha
S
Mascareno
Eduardo
E
Chaqour
Brahim
B
Siddiqui
M A Q
MA
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003433:Crosses, Genetic; D056906:Cyclin T; D042863:Cyclin-Dependent Kinase 9 / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D012313:RNA / Q000096:biosynthesis; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
C503685:Ccnt1 protein, mouse; D056906:Cyclin T; D016213:Cyclins; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; C118642:Hexim1 protein, mouse; D016601:RNA-Binding Proteins; C495678:Slc2a1 protein, mouse; C495693:Slc2a4 protein, mouse; D014157:Transcription Factors; D012313:RNA; D042863:Cyclin-Dependent Kinase 9; D012319:RNA Polymerase II