Abstract
The positive transcription elongation factor b (P-TEFb) was first identified as a general factor that stimulates transcription elongation by RNA polymerase II (RNAPII), but soon afterwards it turned out to be an essential cellular co-factor of human immunodeficiency virus (HIV) transcription mediated by viral Tat proteins. Studies on the mechanisms of Tat-dependent HIV transcription have led to radical advances in our knowledge regarding the mechanism of eukaryotic transcription, including the discoveries that P-TEFb-mediated elongation control of cellular transcription is a main regulatory step of gene expression in eukaryotes, and deregulation of P-TEFb activity plays critical roles in many human diseases and conditions in addition to HIV/AIDS. P-TEFb is now recognized as an attractive and promising therapeutic target for inflammation/autoimmune diseases, cardiac hypertrophy, cancer, infectious diseases, etc. In this review article, I will summarize our knowledge about basic P-TEFb functions, the regulatory mechanism of P-TEFb-dependent transcription, P-TEFb’s involvement in biological processes and diseases, and current approaches to manipulating P-TEFb functions for the treatment of these diseases.
Highlights
Eukaryotic transcription by RNA polymerase II (RNAPII) is a highly orchestrated process regulated at multiple steps, including initiation, promoter clearance, elongation, co-transcriptional processing of nascent transcripts, termination, mRNA cleavage and polyadenylation [1,2,3,4]
Cyclins T1 (CycT1), T2a (CycT2a), or T2b (CycT2b) and cyclin-dependent kinase 9 (CDK9) plays a central role in stimulating transcriptional elongation by phosphorylating serine residues at position 2 (Ser-2) of the conserved heptapeptide repeats (YSPTSPS) of the RNAPII C-terminal domain (CTD) and negative transcription elongation factors (N-Tefs) [11,12,13,14,15,16]
Since positive transcription elongation factor b (P-TEFb) functions via direct interaction with viral and cellular transcription factors (TFs) involved in various human diseases and conditions, P-TEFb is recognized as an excellent drug target for infectious diseases, inflammation/autoimmune diseases, cardiac hypertrophy, and cancer [17,18,19]
Summary
Eukaryotic transcription by RNA polymerase II (RNAPII) is a highly orchestrated process regulated at multiple steps, including initiation, promoter clearance, elongation, co-transcriptional processing of nascent transcripts, termination, mRNA cleavage and polyadenylation [1,2,3,4]. Rapid development of genome-wide transcriptome analysis has revealed that elongation is a critical regulatory step of transcription [5,6,7,8,9,10]. Cyclins T1 (CycT1), T2a (CycT2a), or T2b (CycT2b) and CDK9 plays a central role in stimulating transcriptional elongation by phosphorylating serine residues at position 2 (Ser-2) of the conserved heptapeptide repeats (YSPTSPS) of the RNAPII C-terminal domain (CTD) and negative transcription elongation factors (N-Tefs) [11,12,13,14,15,16]. I would like to provide an overview of the structure and function of P-TEFb, human disease models where P-TEFb plays a critical role, current attempts to manipulate P-TEFb functions, and potential problems and solutions for development of effective and specific P-TEFb inhibitors
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