E. Nabeyrat et al., Retinoic acid protects against hyperoxia-mediated cell-cycle arrest of lung alveolar epithelial cells by preserving late G1 cyclin activities, AM J RESP C, 25(4), 2001, pp. 507-514
Citations number
36
Categorie Soggetti
da verificare
Journal title
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
The epithelium of the lung alveolus is a major target for oxidant injury, a
nd its proper repair after injury is dependent on the proliferative respons
e of the alveolar epithelial type 2 cells. Recently, we have provided evide
nce that retinoic acid (RA) stimulates proliferation of type 2 cells. In th
e present study, we examined the effects of RA on the proliferative respons
e of alveolar type 2 cells exposed to elevated oxygen (O-2). We showed that
pretreatment by RA was able to prevent the growth arrest and cell loss Of
O-2-exposed cells. To gain insights into the mechanisms involved, we studie
d the effects of RA on the cyclin-dependent kinase (CDK) system. The activi
ty of cyclin E-CDK2 complex was found to be decreased in O-2-exposed cells.
Interestingly, this decrease was no longer observed when cells were pretre
ated with RA. Analysis of p21(CIP1), an inhibitor of CDK, revealed an incre
ased expression in O-2-exposed cells that was no longer observed in cells t
reated with RA. These effects were associated with a reduced association of
p21(CIP1) with cyclin E-CDK2 complexes in the presence of RA. In addition,
studies of Smad activity strongly suggest that the mechanisms through whic
h RA preserves late G(1) cyclin-CDK complex activity may involve interferen
ce with the transforming growth factor-beta signaling pathway.