Transforming growth factor beta stimulates the human immunodeficiency virus 1 enhancer and requires NF-kappaB activity.
Transforming growth factor beta (TGF-beta) is the prototype of a large superfamily of signaling molecules involved in the regulation of cell growth and differentiation. In certain patients infected with human immunodeficiency virus type 1 (HIV-1), increased levels of TGF-beta promoted the production of virus and also impaired the host immune system. In an effort to understand the signaling events linking TGF-beta action and HIV production, we show here that TGF-beta can stimulate transcription from the HIV-1 long terminal repeat (LTR) promoter through NF-kappaB binding sites in both HaCaT and 300.19 pre-B cells. When introduced into a minimal promoter, NF-kappaB binding sites supported nearly 30-fold activation from the luciferase reporter upon TGF-beta treatment. Electrophoretic mobility shift assay indicated that a major factor binding to the NF-kappaB site is the p50-p65 heterodimeric NF-kappaB in HaCaT cells. Coexpression of Gal4-p65 chimeric proteins supported TGF-beta ligand-dependent gene expression from a luciferase reporter gene driven by Gal4 DNA binding sites. NF-kappaB activity present in HaCaT cells was not affected by TGF-beta treatment as judged by the unchanged DNA binding activity and concentrations of p50 and p65 proteins. Consistently, steady-state levels of IkappaB alpha and IkappaB beta proteins were not changed by TGF-beta treatment. Our results demonstrate that TGF-beta is able to stimulate transcription from the HIV-1 LTR promoter by activating NF-kappaB through a mechanism distinct from the classic NF-kappaB activation mechanism involving the degradation of IkappaB proteins.
Li
J M
JM
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27708, USA.
Shen
X
X
Hu
P P
PP
Wang
X F
XF
D001402:B-Lymphocytes / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D004742:Enhancer Elements, Genetic / Q000235:genetics; D015658:HIV Infections / Q000235:genetics* / Q000378:metabolism; D016325:HIV Long Terminal Repeat / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D016328:NF-kappa B; D016212:Transforming Growth Factor beta