Positive transcription elongation factor b activity in compensatory myocardial hypertrophy is regulated by cardiac lineage protein-1.

Abstract

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.

• Authors: Jorge Espinoza-Derout, Michael Wagner, Louis Salciccioli, Jason M Lazar, Sikha Bhaduri, Eduardo Mascareno, Brahim Chaqour, M A Q Siddiqui
• Journal: Circulation research (Circ Res) Vol. 104 Issue 12 Pg. 1347-54 (Jun 19 2009) ISSN: 1524-4571 [Electronic] United States
• PMID: 19443839 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Ccnt1 protein, mouse
• Cyclin T
• Cyclins
• Glucose Transporter Type 1
• Glucose Transporter Type 4
• Hexim1 protein, mouse
• RNA-Binding Proteins
• Slc2a1 protein, mouse
• Slc2a4 protein, mouse
• Transcription Factors
• RNA
• Cyclin-Dependent Kinase 9
• RNA Polymerase II

Topics

• Animals
• Cardiomyopathy, Dilated (genetics, metabolism, pathology)
• Crosses, Genetic
• Cyclin T
• Cyclin-Dependent Kinase 9 (genetics, metabolism)
• Cyclins (genetics, metabolism)
• Disease Models, Animal
• Glucose Transporter Type 1 (genetics, metabolism)
• Glucose Transporter Type 4 (genetics, metabolism)
• Humans
• Male
• Mice
• Mice, Knockout
• Myocytes, Cardiac (metabolism, pathology)
• RNA (biosynthesis)
• RNA Polymerase II (genetics, metabolism)
• RNA-Binding Proteins
• Transcription Factors (genetics, metabolism)