APOPTOSIS WAS PROMOTED AT A NONPERMISSIVE TEMPERATURE IN DNA REPLICATION-DEFECTIVE TEMPERATURE-SENSITIVE MUTANTS OF MOUSE FM3A CELLS

Apoptosis was promoted at the nonpermissive temperature in some temper ature-sensitive (ts) mutant strains of mouse FM3A cells deficient in i nitiation of DNA replication. We examined expression of cell cycle reg ulation genes in the four ts mutant strains and found that two strains , tsFT107 and tsFT111, exhibited marked accumulation of p53 protein by a posttranscriptional mechanism at 16 h after temperature upshift. Th ese two strains also exhibited high levels of p21 mRNA expression, rep ression of cyclin A and D1 mRNAs, and obvious accumulation of underpho sphorylated retinoblastoma protein. Only these two strains died by apo ptosis at day 3 after up-shift, although no change was observed in the level of bar mRNA. These results suggest the existence of two types o f responses after temperature up-shift in the four temperature-sensiti ve cell strains of the initiation of DNA replication: one type directs inappropriate DNA replication that then may produce endogenous DNA da mage, p53-mediated cell cycle arrest, and subsequent apoptosis, while the other type exhibits only the p53-independent cell cycle arrest. (C ) 1998 Academic Press.