NF-κB Binds P-TEFb to Stimulate Transcriptional Elongation by RNA Polymerase II (original) (raw)

scription, thus allowing for productive viral replication. Indeed, potent inhibitors of P-TEFb, such as 5,6-Departments of Medicine, Microbiology, and Immunology Dichloro-1-␤-D-ribofuranosylbenzimidazole (DRB) and flavopiridol, block the elongation of transcription as well University of California at San Francisco San Francisco, California 94143 as the production of viral particles in infected cells (Price, 2000; Chao et al., 2000). The central member of the mammalian Rel/NF-B family is NF-B (Barkett and Gilmore, 1999). The major Cambridge, Massachusetts 02139 3 Institute of Biochemistry form of NF-B exists as a heterodimer between RelA and p50. In the inactive cytoplasmic form, the RelA/ Medical Faculty of the University of Ljubljana Vrazov trg 2 p50 heterodimer binds to the inhibitor IB protein. In response to a wide range of stimuli, the two conserved 1000 Ljubljana Republic of Slovenia serine residues in the N-terminal domain of IB become phosphorylated, resulting in its polyubiquitination and subsequent degradation (Karin and Ben-Neriah, 2000). Consequently, NF-B translocates to the nucleus and Summary stimulates the expression of its target genes. Although P-TEFb is essential for the regulation of To stimulate transcriptional elongation of HIV-1 genes, the transactivator Tat recruits the positive transcrip-genes involved in the heat shock response (Lis et al., 2000) and in antigen processing and presentation (Kana-tion elongation factor b (P-TEFb) to the initiating RNA polymerase II (RNAPII). We found that the activation zawa et al., 2000), our knowledge about the roles that P-TEFb plays in other cellular processes remains ob-of transcription by RelA also depends on P-TEFb. Similar to Tat, RelA activated transcription when tethered scure. Since members of the Rel/NF-B family regulate growth, transformation, and apoptosis of cells (Barkett to RNA. Moreover, TNF-␣ triggered the recruitment of P-TEFb to the NF-B-regulated IL-8 gene. While the and Gilmore, 1999), we were intrigued by the ability of flavopiridol to counteract proliferation and induce cell formation of the transcription preinitiation complex (PIC) remained unaffected, DRB, an inhibitor of P-TEFb, death (Chao et al., 2000). Further indications that NF-B can regulate the elongation of transcription via P-TEFb prevented RNAPII from elongating on the IL-8 gene. Remarkably, DRB inhibition sensitized cells to TNF-␣-come from studies where HIV-1 without a functional TAR can replicate in TNF-␣-stimulated infected cells (Duh et induced apoptosis. Thus, NF-B requires P-TEFb to stimulate the elongation of transcription and P-TEFb al., 1989; Harrich et al.,