V. Cazals et al., Role for NF-kappa B in mediating the effects of hyperoxia on IGF binding protein 2 promoter activity in lung alveolar epithelial cells, BBA-MOL CEL, 1448(3), 1999, pp. 349-362
Citations number
53
Categorie Soggetti
Cell & Developmental Biology
Journal title
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
The surface of the pulmonary alveolus is a major target for oxidant injury,
and its proper repair following injury is dependent on the proliferative r
esponse of the stem cells of the alveolar epithelium, the type 2 cells. In
previous studies on the mechanisms controlling this response, we have docum
ented involvement of several components of the IGF system, and mainly of th
e IGF binding protein-2 (IGFBP-2). We have provided evidence that this bind
ing protein was associated with inhibition of DNA synthesis of type 2 cells
exposed to oxidants and that its expression was regulated mostly at the le
vel of transcription. In the present study, we focused on the factors invol
ved in this regulation. From examination of the IGFBP-2 gene promoter seque
nce which revealed the presence of four potential binding sites for transcr
iption factors of the NF-kappa B/Rel family, we hypothesized that NF-kappa
B might be involved in the transcriptional activation of IGFBP-2 in oxidant
-exposed cells. Data reported herein demonstrated that NF-kappa B activated
IGFBP-2 promoter in transient transfection assays, and that exposure of ce
lls to hyperoxia was associated with accumulation of the active form of NF-
kappa B, Using gel shift analysis, we documented in O-2-treated cells an in
creased binding to the four NF-kappa B binding sites, We also showed that a
ccumulation of NF-kappa B was associated with a decrease in the inhibitory
molecule I kappa B-alpha, Based on the current knowledge on NF-kappa B regu
lation, it is likely that in a number of situations associated with injury
of lung alveolar epithelial cells signaling events involving accumulation o
f NF-kappa B converge to activate IGFBP-2 and to block entry into S phase.
(C) 1999 Elsevier Science B.V. All rights reserved.