SENESCENT WI-38 CELLS FAIL TO EXPRESS EPC-1, A GENE INDUCED IN YOUNG CELLS UPON ENTRY INTO THE G(0) STATE

Recently we reported the isolation of cDNAs for a number of genes that are differentially expressed between nonproliferating early (young) a nd late (senescent) population doubling level (PDL) WI-38 human, fetal lung-derived, fibroblast-like cells. We now demonstrate that one of t hese isolates, EPC-1 (early PDL cDNA-1), derives from an approximately 1.4-kilobase mRNA species that is expressed at a greater-than-or-equa l-to 100-fold higher level in serum-starved, confluent, young versus s imilarly treated senescent WI-38 cells. Complete nucleotide sequence a nalysis of this cDNA confirms its identity with that of a cDNA encodin g a secreted, retinal pigmented epithelium differentiation factor as w ell as similarity of the encoded protein with a number of mammalian se rine protease inhibitors. We show that EPC-1 expression is associated with Go growth arrest in WI-38 cells. The mRNA readily accumulates in density-arrested and/or serum-starved young cells but not in log phase , low density young cells. In contrast, EPC-1 transcript abundance and expression of the encoded, secreted protein are both negligible in se nescent WI-38 cells under all culture conditions tested. These finding s support the hypothesis that senescent WI-38 cells exhibit a state of growth arrest fundamentally distinct from that of quiescent (G0) youn g cells.