Differentiation of mammalian cells implies cessation of DNA replication and cell proliferation; the potential controls of this coupling are examined here. It is clear that the known or proposed mechanisms of down-regulation of replicative cellular activities vary in different lineages of cell differentiation, and occur in all phases of the cell cycle. In G1 these regulators include p21/Cip1 or p27/Kip1, pRb, and p53; the novel, recently reported mechanisms of their action are summarized. In S phase the availability of nucleotide precursors, the origin recognition complex (ORC), and other replication proteins may be important in differentiation, and in G2 phase the cdc2/cyclin B complex and replication licensing factors determine normal G2 traverse versus an arrest or polyploidisation. Other replication-related mechanisms include transcription factors, e.g., Sp1, telomerase, and nuclear matrix changes. Thus, differentiation alters the activity not only of the various checkpoint proteins, but also of the components of the replicative machinery itself.
Copyright 1999 Academic Press.