Am. J. Respir. Cell Mol. Biol., Vol 12, No. 1, Jan 1995, 95-103.
Differential expression of cyclin D2 and cdc2 genes in proliferating and nonproliferating alveolar epithelial cells
F Wu, S Buckley, KC Bui and D Warburton
Department of Pediatrics, Childrens Hospital of Los Angeles, University of Southern California School of Medicine 90027.
Alveolar epithelial cells (AEC) proliferate during embryonic and fetal
life, while in the adult lung AEC form a highly differentiated population
that does not usually divide. Herein, we tested the hypothesis that
differential expression of specific cell cycle control genes may occur
during AEC development and transformation. We compared normal rat AEC in
primary culture with transformed AEC for the expression of D-type G1
cyclins and cyclin-dependent protein kinases (cdc2 and cdk2). Cyclin D1
mRNA and protein were expressed at comparable levels in both normal rat AEC
and in transformed AEC. In contrast, high levels of cyclin D2 mRNA and
protein expression were only observed in normal 19-day fetal rat AEC and in
transformed mink Mv1Lu cells derived from fetal mink lung epithelium.
Moreover, treatment either with antisense oligodeoxynucleotides directed
against cyclin D2 mRNA or with genistein (a tyrosine kinase inhibitor)
caused significant inhibition of [3H]thymidine incorporation into DNA as
well as inhibition of cyclin D2 expression in normal 19-day fetal rat AEC.
p34cdc2 (but not p33cdk2 or p34cdk4) was expressed at progressively
decreasing levels with corresponding histone H1 kinase activities during
rat AEC development (19-day fetal > 21-day fetal > 13-day postnatal
> adult rat AEC). The levels of p34cdc2 histone H1 kinase activity were
significantly up-regulated or amplified in adult rat type 2 AEC following
hyperoxic injury and repair and in transformed AEC. Collectively, these
data support an important functional role for cyclin D2 and cdc2 genes in
determining the proliferative versus nonproliferative phenotype of AEC
during lung development, injury and repair, and transformation.
