Retinoic acid-induced proliferation of lung alveolar epithelial cells is linked to p21(CIP1) downregulation.
Retinoids, including retinol and retinoic acid (RA) derivatives, have been shown to be involved in the processes of lung development as well as of lung repair after injury. Recently, we have provided evidence that RA could stimulate proliferation of lung alveolar type 2 epithelial cells (E. Nabeyrat, V. Besnard, S. Corroyer, V. Cazals, and A. Clement. Am. J. Physiol. Lung Cell. Mol. Physiol. 275: L71-L79, 1998). To gain some insight into the mechanisms involved in the mitogenic action of RA, we focused in the present study on the effects of RA on the expression of G(1) phase cyclins and their cell cycle-dependent kinases (Cdks). Experiments were performed with serum-deprived cells cultured in the absence and presence of RA. The results showed no effects of RA on the expression of either cyclins or Cdks. In contrast, RA treatment was found to prevent the decrease in cyclin E-Cdk2 activity observed when cells were growth arrested by serum deprivation. The observation that changes in cyclin E-Cdk2 activity were not associated with modifications in the amount of complexes formed led to the suggestion that the Cdk inhibitory protein (CKI) was involved. Study of the CKI p21(CIP1) revealed marked differences in its expression in the absence and presence of RA, with a dramatic downregulation observed in RA-treated cells. Interestingly, immunoprecipitation experiments provided evidence that the decreased levels of p21(CIP1) were associated with a reduced interaction of this CKI with cyclin E-Cdk2 complexes. These data together with previous results obtained in various situations of type 2 cell growth arrest emphasize the role of p21(CIP1) in the control of lung alveolar epithelial cell proliferation.
Nabeyrat
E
E
Departement de Pneumologie Pediatrique, Institut National de la Santé et de la Recherche Médicale Unité 515, Hôpital Trousseau Assistance Publique-Hôpitaux de Paris, Université Paris VI, 75012 Paris, France.
Corroyer
S
S
Epaud
R
R
Besnard
V
V
Cazals
V
V
Clement
A
A
D000818:Animals; D042846:CDC2-CDC28 Kinases; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism*; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D016193:G1 Phase / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D014212:Tretinoin / Q000494:pharmacology*
C493958:Cdkn1a protein, rat; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011518:Proto-Oncogene Proteins; D014212:Tretinoin; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; C495903:Cdk4 protein, rat; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases