Abstract
p300 is a key protein, which determines acceleration or deceleration of signal transduction. Recently, renal proximal tubular cells have not only been found to be a harboring site for HIV-1 but have also been shown to undergo apoptosis in response to HIV-1 exposure. Both HIV-1 and its envelop glycoprotein, i.e. gp120, triggered tubular cell apoptosis in the same magnitude. In the present study, we evaluated the role of p300 in gp120-induced tubular cell apoptosis and associated downstream signaling. We have demonstrated that by transient transfection assays, p300 significantly increases susceptibility of human proximal renal tubular HK-2 cells to apoptosis triggered by HIV-1 gp120. A mutant p300, missing the E1A/TFIIB binding site, fails to produce such sensitization potential. Smad7 and an anti-TGF-beta antibody rescue the p300 sensitization. Furthermore, p300 and HIV-1 gp120 synergistically increase TGF-beta, ATF-2 and activating protein-1 (AP-1) expression. In addition, HIV-1 gp120 results in phosphorylation of Smad2 and decreases c-Jun. These findings suggest that p300 acts as a potent transcriptional cofactor in HIV-1 gp120-induced apoptosis via TGF-beta and Smad signaling.
2006 S. Karger AG, Basel.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antibodies / pharmacology
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Apoptosis / physiology*
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Binding Sites / physiology
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Cell Line
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Drug Synergism
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E1A-Associated p300 Protein / metabolism
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HIV Envelope Protein gp120 / pharmacology*
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Humans
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Kidney Tubules, Proximal / cytology
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Kidney Tubules, Proximal / drug effects
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Kidney Tubules, Proximal / metabolism*
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Kidney Tubules, Proximal / physiology
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Phosphorylation / drug effects
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Protein Structure, Tertiary / physiology
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Signal Transduction / physiology*
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Smad Proteins / metabolism*
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Smad2 Protein / metabolism
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Smad7 Protein / metabolism
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Transcription Factor AP-1 / drug effects
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Transcription Factor AP-1 / physiology
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Transcription Factor TFIIB / metabolism
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Transfection
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Transforming Growth Factor beta / immunology
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Transforming Growth Factor beta / metabolism*
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p300-CBP Transcription Factors / genetics
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p300-CBP Transcription Factors / pharmacology
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p300-CBP Transcription Factors / physiology*
Substances
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Antibodies
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HIV Envelope Protein gp120
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SMAD2 protein, human
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SMAD7 protein, human
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Smad Proteins
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Smad2 Protein
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Smad7 Protein
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Transcription Factor AP-1
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Transcription Factor TFIIB
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Transforming Growth Factor beta
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E1A-Associated p300 Protein
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p300-CBP Transcription Factors