Cell growth-regulated expression of mammalian MCM5 and MCM6 genes mediatedby the transcription factor E2F

Initiation of DNA replication requires the function of MCM gene products, w hich participate in ensuring that DNA replication occurs only once in the c ell cycle, Expression of all mammalian genes of the MCM family is induced b y growth stimulation, unlike yeast, and the mRNA levels peak at G1/S bounda ry, In this study, we examined the transcriptional activities of isolated h uman MCM gene promoters. Human MCMS and MCM6 promoters with mutation in the E2F sites failed in promoter regulation following serum stimulation and ex ogenous E2F expression. In addition, me identified a novel E2F-Like sequenc e in human MCM6 promoter which cooperates with the authentic E2F sites in E 2F-dependent regulation. Forced expression of E2F1 could induce expression of all members of the endogenous MCM genes in rat embryonal fibroblast REF5 2 cells. Our results demonstrated that the growth-regulated expression of m ammalian MCM5 and MCM6 genes, and presumably other MCM members, is primaril y regulated by E2F through binding to multiple E2F sites in the promoters.