NEGATIVE CONTROL OF CELL-PROLIFERATION IN EUKARYOTES

Control over cell growth in eukaryotes is predominantly achieved by re gular transition of cells from proliferation to rest and vice versa as a result of a co-ordinated inter-relationship between intracellular g rowth inhibitors and extracellular growth stimulators (mitogens). The ability to cease and resume growth on demand implies the existence of a refined intracellular regulatory network including both positive and negative control elements. We review here evidence that resting cells are able to produce molecules with antiproliferative activity, some o f which behave as short-lived repressor proteins. A number of genes co ding for growth inhibitory molecules have been identified. However, it is not yet certain whether the same molecules ensure the maintenance of a resting state. It has become apparent that immediate growth arres t or growth resumption require not only a rapid production of inhibito rs and stimulators but also their biochemical transformation (e.g. pho sphorylation or dephosphorylation) and/or translocation within the cel l, whereby one and the same molecule can be a growth inhibitor or fulf il some other function in the cell cycle, according to circumstances o r context. At present, three levels of negative cell growth control ca n be tentatively outlined: 1 rapid appearance of growth inhibitory mol ecules to bring about temporary arrest at critical checkpoints of the proliferative cycle; 2 transition of a cell to proliferative rest with continuous production of growth inhibitor(s); 3 long-lasting maintena nce of the resting state provided for by complex intracellular changes not connected with production of growth inhibitor(s).