Determining to divide: how do cells decide?

Abstract

A cell's decision to divide must be regulated with the highest fidelity. Otherwise, abnormalities occurring in the replication of genetic material and cytokinesis would be incompatible with life. It has been known for almost a century that cells comprising a population undergo cellular division at extremely variable rates, even though genetically identical cell clones have been examined. Studies with T lymphocytes at the single cell level have revealed that the rate of cellular division is determined by the accumulation of a critical number of ligand-triggered interleukin-2 (IL2) receptors at the cell surface throughout the G(1) phase of the cell cycle. Thus, the cell "counts" the number of triggered IL2 receptors, and only decides to divide when the critical number has been attained. This information is then transferred to the cellular interior via intracellular sensors comprised of D-type cyclins, which ultimately determine when the cell surpasses the "Restriction Point" in late G(1), and which commits the cell irrevocably to initiate DNA replication. Beyond the R-point, the cell assembles a definite number of macromolecular pre-replication complexes (Pre-RCs) comprised of at least 6 distinct proteins at sites of the origin of replication on DNA. Complete assembly of the Pre-RCs is a prerequisite for their subsequent disassembly, which must occur before the initiation of DNA strand replication, and which occurs asynchronously throughout the S-phase of the cell cycle and only terminates when the entire DNA has been duplicated. Thus, the fidelity of the decision to divide is exquisitely regulated by macromolecular mechanisms initiated at the cell surface and transferred to the cellular interior so that the cell can make the decision in a quantal (all-or-none) fashion. The question before us is how this quantal decision is made at the molecular level. The available data indicate that the assembly and disassembly of a definite number of large multicomponent macromolecular complexes make the quantal decisions. Here, it is postulated that all fundamental cellular decisions, i.e. survival, death, proliferation and differentiation, are regulated in this fashion. It remains to be determined how the cell counts the signals it receives, and what the molecular forces are that dictate the behavior of macromolecular complexes.

Keywords: DNA replication; Janus kinases (JAK); Restriction point (R-point); cell cycle; cyclin; cyclin-dependent kinases (CDK); interleukin-2 (IL2); quantal; retinoblastoma (Rb) proteins.