Retinoic acid protects against hyperoxia-mediated cell-cycle arrest of lung alveolar epithelial cells by preserving late G1 cyclin activities.
The epithelium of the lung alveolus is a major target for oxidant injury, and its proper repair after injury is dependent on the proliferative response of the alveolar epithelial type 2 cells. Recently, we have provided evidence that retinoic acid (RA) stimulates proliferation of type 2 cells. In the present study, we examined the effects of RA on the proliferative response 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 studied the effects of RA on the cyclin-dependent kinase (CDK) system. The activity 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 pretreated with RA. Analysis of p21(CIP1), an inhibitor of CDK, revealed an increased expression in O(2)-exposed cells that was no longer observed in cells treated 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 which RA preserves late G(1) cyclin-CDK complex activity may involve interference with the transforming growth factor-beta signaling pathway.
Nabeyrat
E
E
Département de Pneumologie Pédiatrique-INSERM U515, Hôpital Trousseau, 26, Ave Dr. Netter, 75012 Paris, France.
Corroyer
S
S
Besnard
V
V
Cazals-Laville
V
V
Bourbon
J
J
Clement
A
A
D000818:Animals; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D019927:Cyclin E / Q000187:drug effects / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000187:drug effects / Q000378:metabolism; D016213:Cyclins / Q000187:drug effects / Q000378:metabolism*; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D018496:Hyperoxia / Q000188:drug therapy / Q000517:prevention & control*; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020545:Respiratory Mucosa / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
C493958:Cdkn1a protein, rat; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016212:Transforming Growth Factor beta; D014212:Tretinoin; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D010100:Oxygen