Pregnancy-specific glycoproteins (PSGs) comprise a family of highly similar polypeptides encoded by 11 transcriptionally active genes that compactly cluster on band 19q13.2. All members of the PSG family were found to be markedly up-regulated by addition of 5-bromodeoxyuridine in HeLa cells. Similarly, all of the members were markedly up-regulated during replicative senescence in normal human fibroblasts. Promoter analysis of the PSG1, 4, and 11 genes in HeLa cells did not reveal a cis-regulatory element responsive to 5-bromodeoxyuridine in their 5'-flanking sequences. These results suggest that the PSG genes are regulated at a level of higher order chromatin structure besides by a signal of pregnancy.