Regulation of the Eukaryotic Cell Cycle

Abstract

Prior to the 1950s, the first indication that a cell was committed to divide was the onset of mitosis itself, marked by the dramatic events of chromosome condensation, nuclear envelope breakdown and spindle formation. With the advent of suitable radioactive tracers, it soon became clear that events relevant to cell division, notably DNA replication, actually began many hours before mitosis (Howard and Pelc 1953). This led to the subdivision of interphase into the now familiar phases of the cell cycle, namely: G₁, the gap between mitosis and the start of DNA replication; S phase, the period of DNA synthesis; and G₂, the gap between the completion of DNA synthesis and the onset of mitosis, M. Following measurements of the duration of each phase, it quickly became apparent that for many eukaryotic cell types (and certainly, for the somatic cells of vertebrates), regulation of the cycle occurs primarily in G₁ (Smith 1982). Thus, though not invariant, the duration of S + G₂ + M generally changes far less than does the duration of G₁ with changes in proliferation rate. Furthermore, cells which cease proliferation, either reversibly (e.g. hepatocytes, lymphocytes) or permanently (e.g. neurones), come to arrest in G₁. Passage through G₁ requires an adequate nutritional environment and, in the case of vertebrate somatic cells, stimulation by an appropriate set of polypeptide growth factors. However, once past a certain point (referred to variously as the restriction point, or START), the cell is committed to divide and removal of nutrients or growth factors fails to prevent entry into S phase (Hartwell 1974; Pardee 1974).