Retinoic acid-induced proliferation of lung alveolar epithelial cells is linked to p21(CIP1) downregulation

Retinoic acid-induced proliferation of lung alveolar epithelial cells is li nked to p21(CIP1) downregulation. Am. J. Physiol. Lung Cell. Mel. Physiol. 278: L42-L50, 2000. Retinoids, including retinol and retinoic acid (RA) der ivatives, have been shown to be involved in the processes of lung developme nt as well as of lung repair after injury. Recently, we have provided evide nce that RA could stimulate proliferation of lung alveolar type 2 epithelia l cells (E. Nabeyrat, V. Besnard, S. Corroyer, V. Cazals, and A. Clement. A m. J. Physiol. Lung Cell. Mol. Physiol. 275: L71-L79, 1998). To gain some i nsight into the mechanisms involved in the mitogenic action of RA, we focus ed in the present study on the effects of RA on the expression of G(1) phas e cyclins and their cell cycle-dependent kinases (Cdks). Experiments were p erformed 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 cy clin E-Cdk2 activity observed when cells were growth arrested by serum depr ivation. The observation that changes in cyclin E-Cdk2 activity were not as sociated with modifications in the amount of complexes formed led to the su ggestion that the Cdk inhibitory protein (CKI) was involved. Study of the C KI p21(CIP1) revealed marked differences in its expression in the absence a nd presence of RA, with a dramatic downregulation observed in RA-treated ce lls. Interestingly, immunoprecipitation experiments provided evidence that the decreased levels of p21(CIP1) were associated with a reduced interactio n of this CKI with cyclin E-Cdk2 complexes. These data together With previo us results obtained in various situations of type 2 cell growth arrest emph asize the role of p21(CIP1) , the control of lung alveolar epithelial cell proliferation.