MinireviewCell differentiation and proliferation—simultaneous but independent?
Section snippets
The possible involvement of cyclin-dependent kinase inhibitors in initiating differentiation
Cyclin-dependent protein kinases (CDKs), their regulatory cyclins, and CDK inhibitors (CDKIs) are primary regulators of the cell cycle [7], [8]. Given the purported link between cell cycle exit and differentiation, the identification of CDKIs seemed to offer a useful starting point for identifying initiators of differentiation [9]. CDKIs are of two types: INK4 proteins (p16INK4A, p15INK4B, and p19INK4C) interfere with cyclin D binding to CDK4 and CDK6 and so inhibit CDK activity [10], [11]; and
“Maturation divisions” accompany differentiation but are controlled independently
During terminal differentiation, committed erythroid progenitor cells (CFU-E: colony forming unit—erythroid) and model cell lines such as murine erythroleukaemia (MEL) undergo ∼5–6 divisions before permanently leaving the cell cycle [27], [28]. These maturation divisions are different from the cell cycles involved in “normal” cell proliferation. In chicken erythroid progenitors, for instance, the period needed to transit the cell cycle progressively shortens as the synthesis of haemoglobin and
“Uncoupling” differentiation from proliferation
The information summarised so far establishes that a few rounds of proliferation often accompanies the commitment of progenitor cells to terminal differentiation. Are these maturation divisions essential for the cells to differentiate successfully, or might cells be able to differentiate without undergoing any cell cycle progression? It has been suggested that progressive remodeling of chromatin during these postcommitment cell cycles facilitates the sequential emergence of differentiated
Similar patterns in immune cells
Most peripheral blood T lymphocytes and B lymphocytes are out of cycle in G0, and the expansion and maturation of antigen-simulated clones are among classical situations that involve concurrent cell proliferation and differentiation [48]. This probably serves to maximise the mature effector cell yield in vivo.
Circulating T lymphocytes typically exist in a prolonged G0 state, and their interaction with antigen-presenting cells leads them to initiate several rounds of division. This selectively
Concluding comments
The succession of activities that occurs through the various phases of the cell cycle maps out the “timetable” followed by proliferating cells. So to what extent might the cycling of cells — or at least their admission to particular cell cycle phases—be necessary for the correct control of other complex cell processes such as increase in size, differentiation, or apoptosis? The main conclusion from the studies discussed above is that differentiation is generally not coupled in any tight manner
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