title: p300 modulates HIV-1 gp120-induced apoptosis in human proximal tubular cells: associated with alteration of TGF-beta and Smad signaling.
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.
authors.affiliation: Division of Nephrology, Department of Medicine, Long Island Jewish Medical Center, The Long Island Campus, Albert Einstein College of Medicine, New Hyde Park, NY, USA.
authors.forename: Aditi A
authors.initials: AA
authors.lastname: Kapasi
authors.forename: Saijun
authors.initials: S
authors.lastname: Fan
authors.forename: Pravin C
authors.initials: PC
authors.lastname: Singhal
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D001665:Binding Sites / Q000502:physiology; D002460:Cell Line; D004357:Drug Synergism; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000502:physiology; D035581:Transcription Factor TFIIB / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*
chemical_list: D000906:Antibodies; D015699:HIV Envelope Protein gp120; C497782:SMAD2 protein, human; C497806:SMAD7 protein, human; D051785:Smad Proteins; D051899:Smad2 Protein; D051906:Smad7 Protein; D018808:Transcription Factor AP-1; D035581:Transcription Factor TFIIB; D016212:Transforming Growth Factor beta; D050881:E1A-Associated p300 Protein; D050880:p300-CBP Transcription Factors