Nuclear receptor coactivator p160 proteins enhance the HIV-1 long terminal repeat promoter by bridging promoter-bound factors and the Tat-P-TEFb complex

Tomoshige Kino, Olga Slobodskaya, George N. Pavlakis, George P. Chrousos

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

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 κB-responsive elements, most likely via NF-κB, with which it also associates through its coactivator motifs (LXXLL motifs, "NR boxes"). Indeed, the Tat-stimulated κB-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-κB 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.

Original languageEnglish
Pages (from-to)2396-2405
Number of pages10
JournalJournal of Biological Chemistry
Volume277
Issue number4
DOIs
Publication statusPublished - 25 Jan 2002
Externally publishedYes

Fingerprint

Positive Transcriptional Elongation Factor B
Nuclear Receptor Coactivators
HIV Long Terminal Repeat
Terminal Repeat Sequences
HIV-1
Mouse mammary tumor virus
Cyclin T
Viruses
Tumors
Proteins
Transcription
Elongation
Molecules
Trans-Activators
Glucocorticoid Receptors
Carcinogens
Chemical activation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Nuclear receptor coactivator p160 proteins enhance the HIV-1 long terminal repeat promoter by bridging promoter-bound factors and the Tat-P-TEFb complex. / Kino, Tomoshige; Slobodskaya, Olga; Pavlakis, George N.; Chrousos, George P.

In: Journal of Biological Chemistry, Vol. 277, No. 4, 25.01.2002, p. 2396-2405.

Research output: Contribution to journalArticle

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T1 - Nuclear receptor coactivator p160 proteins enhance the HIV-1 long terminal repeat promoter by bridging promoter-bound factors and the Tat-P-TEFb complex

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N2 - 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 κB-responsive elements, most likely via NF-κB, with which it also associates through its coactivator motifs (LXXLL motifs, "NR boxes"). Indeed, the Tat-stimulated κB-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-κB 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.

AB - 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 κB-responsive elements, most likely via NF-κB, with which it also associates through its coactivator motifs (LXXLL motifs, "NR boxes"). Indeed, the Tat-stimulated κB-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-κB 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.

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