Dysregulation of Positive Transcription Elongation Factor b and Myocardial Hypertrophy

Abstract

See related articles, pages 1347–1354 Prolonged stimulus of the adult heart by hypertension, arrhythmias, or other pathogenic conditions can result in myocardial hypertrophy and subsequently heart failure. Hypertrophy is characterized by an increase in the size of cardiomyocytes and this is associated with an elevated rate of RNA synthesis and protein synthesis in these cells. Although mechanisms responsible for this increased RNA and protein synthesis remain to be fully elucidated, an article by Espinoza-Derout et al1 in this issue of Circulation Research provides additional evidence that dysregulation of the general RNA polymerase II elongation factor known as P-TEFb can be an important mechanism in the development of hypertrophy. RNA polymerase II transcribes all protein-coding genes, and its function is regulated both at the levels of transcription initiation and elongation. Initiation is positively regulated by transcription factors that bind to specific cis -regulatory sequences in the promoters of individual genes. These transcription factors function to recruit both coactivators and the RNA polymerase II complex and transcription initiation is enhanced at these genes. After initiation, transcriptional elongation can be defective because of the action of 2 negative factors, DSIF and NELF, which limit elongation.2,3 These negative factors may function as a quality control mechanism to ensure capping of nascent mRNA, thereby stabilizing the RNA for subsequent processing events and transcriptional termination.4 Although almost all protein-coding genes appear to undergo some level of constitutive transcription initiation, only a subset actually produce full-length transcripts, indicating that many genes are defective in transcriptional elongation.5 This block to productive elongation is overcome by the action of P-TEFb (positive transcription elongation factor b). P-TEFb is a protein kinase that can hyperphosphorylate the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase. The CTD of mammalian RNA polymerase II contains 52 repeats …