The elongation stage of eukaryotic transcription has only recently been recognized as a highly dynamic and regulated process that couples transcription with other major gene expression events. Our appreciation of its role in controlling gene expression has benefited tremendously from the analysis of a single model system that centers on the mechanism regulating HIV transcriptional elongation. Tat is an essential regulatory protein encoded by the HIV virus. It cooperates with the host cellular cofactor P-TEFb to stimulate the production of the full-length HIV transcripts. Consisting of CDK9 and cyclin T, P-TEFb also functions as a general transcriptional elongation factor globally required for eukaryotic gene expression. It activates transcription by phosphorylating RNA polymerase II, leading to the formation of a highly processive elongation complex. Here, we review recent advances concerning Tat, P-TEFb and their control of HIV elongation. Additionally, we discuss how the studies of P-TEFb impact our understanding of the general control of eukaryotic gene expression at the stage of transcriptional elongation.


In eukaryotic cells, the transcription of messenger RNA (mRNA) from protein-coding genes is performed by RNA polymerase II in a cyclic process consisting of several tightly connected stages designated as pre-

initiation, initiation, promoter clearance, elongation and termination (Shilatifard, 2004; Sims et al., 2004). Over the past two decades, efforts to understand the molecular mechanisms of transcriptional regulation have mainly focused on the assembly of pre-initiation complexes and the initiation process, resulting in the identification of many factors that are required for these early steps of mRNA transcription (Shilatifard, 2004; Sims et al., 2004). In contrast, studies analyzing the elongation stage of transcription have lagged behind, largely due to the lack of an appropriate model system as well as gene-specific elongation factors. For many years, transcriptional elongation has been thought of as repetitive, unregulated additions of ribonucleoside triphosphates to the growing mRNA chain. In addition, the processing of pre-mRNA has been considered as a series of post-transcriptional events separable from the transcription process. Only until recently, it has become increasingly clear that the elongation stage of eukaryotic transcription is a highly regulated process that is capable of not only generating full-length RNA transcripts but also coupling transcription with other major gene expression events such as pre-mRNA capping, splicing, and polyadenylation (Bentley, 1999; Howe, 2002; Kim et al., 2001; Proudfoot et al., 2002; Reines et al., 1999; Shilatifard et al., 2003; Steinmetz, 1997). Moreover, the recent years have also seen great advances in the biochemical analysis of the mechanisms and factors that control the elongation process. Some of the most significant advances have come from studies of one particular HIV-encoded regulatory protein called Tat and its host cellular cofactor P-TEFb (positive transcription elongation factor b). Today, Tat remains the best-characterized gene-specific transcriptional

Corresponding Author: Qiang Zhou, Tel: (510) 643-1697 (Office), (510) 643-0494 (Lab), Fax: (510) 643-6334, E-mail: [email protected]

elongation factor and P-TEFb a Tat-specific cofactor as well as a general elongation factor. These two factors work together to stimulate HIV elongation by modulating the activity of Pol II, resulting in the critical transition from abortive to productive elongation (Garriga and Grana, 2004; Jones, 1997; Price, 2000). In this review, we will focus our attention on novel insights into the mechanisms and factors controlling general and HIV-specific transcriptional elongation with a special emphasis on P-TEFb and Tat. Furthermore, we will examine the contributions of P-TEFb and another elongation factor Tat-SFl in coupling transcription with pre-mRNA splicing. Finally, we will discuss how the activity of P-TEFb as a general elongation factor is regulated and how this regulation may lead to the global control of cell growth and differentiation.

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