Nuclear receptor coactivator p160 proteins enhance the HIV-1 long terminal repeat promoter by bridging promoter-bound factors and the Tat-P-TEFb complex.
We report that p160 nuclear receptor coactivators potentiate the transactivating activity of Tat, the most potent virally encoded transactivator of HIV-1. One of the p160 proteins (GRIP1) is tethered to the HIV-1 long terminal repeat (LTR) through kappaB-responsive elements, most likely via NF-kappaB, with which it also associates through its coactivator motifs (LXXLL motifs, "NR boxes"). Indeed, the Tat-stimulated kappaB-defective HIV-1 LTR had a markedly impaired response to GRIP1, whereas NR box-defective GRIP1 proteins lost part of their Tat coactivator effect on the HIV-1 LTR. Through its N-terminal basic helix-loop-helix and C-terminal domains, GRIP1 binds to the N-terminal region of Tat and to the host cell protein cyclin T1, respectively, which is normally complexed with CDK9 as P-TEFb. Thus, NF-kappaB is crucial for tethering p160 coactivator molecules to the HIV-1 LTR, allowing full activation of this promoter by Tat. Interestingly, cotransfection of Tat, GRIP1, and cyclin T1 enhanced not only the activity of the HIV-1 LTR, but also the glucocorticoid receptor-mediated stimulation of the mouse mammary tumor virus (MMTV) promoter, suggesting that Tat can also attract the P-TEFb complex to the MMTV LTR through GRIP1. Thus, it appears that the coactivator complexes of the HIV-1 and MMTV LTRs both include p160 coactivators and use similar coactivator and elongation complexes for their transcription. Tat may function as an adaptor molecule, efficiently stimulating the processes of transcription initiation and elongation through potentiation of the coupling of p160 coactivators and the P-TEFb complex.
Kino
Tomoshige
T
Pediatric and Reproductive Endocrinology Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892, USA. kinot@mail.nih.gov
Slobodskaya
Olga
O
Pavlakis
George N
GN
Chrousos
George P
GP
D001665:Binding Sites; D056906:Cyclin T; D016213:Cyclins / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005982:Glutathione Transferase / Q000378:metabolism; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000378:metabolism*; D006367:HeLa Cells; D051548:Histone Acetyltransferases; D006801:Humans; D019169:Jurkat Cells; D008156:Luciferases / Q000378:metabolism; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D008954:Models, Biological; D008957:Models, Genetic; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D010957:Plasmids / Q000378:metabolism; D042925:Positive Transcriptional Elongation Factor B; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
C503684:CCNT1 protein, human; C503685:Ccnt1 protein, mouse; D056906:Cyclin T; D016213:Cyclins; C498001:NCOA2 protein, human; D051958:Nuclear Receptor Coactivator 2; D014157:Transcription Factors; D008156:Luciferases; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1; D005982:Glutathione Transferase; D042925:Positive Transcriptional Elongation Factor B; D017346:Protein Serine-Threonine Kinases