Revisiting the relationship of the mammalian G1 phase to cell differentiation.

It is widely held that mammalian cells make a decision in the G1 phase of the division cycle either to proceed through the cell cycle or to di!erentiate and cease growth and division (Hass, 1994; Herwig & Strauss, 1997; Loyer et al., 1996; Rifkind et al., 1996; Sherr, 1995; Wiman, 1993; Zavitz & Zipursky, 1997). This belief was originally derived from the general observation that di!erentiated cells are overwhelmingly (if not completely) cells with a G1-phase amount of DNA. Simply put, it is currently envisioned that cells make a decision in the G1 phase of the division cycle to di!erentiate. After di!erentiation the cells remain &&in the G1 phase'' and do not initiate DNA synthesis. Cells that are undergoing di!erentiation do not enter S, G2, or M phases. Cells that were in the S, G2, and M phases when the initiation signal was received pass through these phases, decide to di!erentiate in the G1 phase, and then do not initiate another S phase. In this way, the current model proposes that a population of di!erentiated cells is produced, with all of the cells having a G1-phase amount of DNA. The proposed existence of a G1-phase decision point for di!erentiation has provided support for the general idea that there are important cell cycle controls residing in the G1 phase of the division cycle. The proposal of a restriction point,