Molecular basis of a control mechanism of DNA synthesis in mammalian cells.

Personal observations made on the model of isoproterenol-stimulated DNA synthesis have pointed out the following: 1) cell hypertrophy precedes constantly the onset of DNA synthesis; 2) the length of the G1 phase is mass-dependent; 3) accumulation of ribosomes is needed for cell progress through G1; 4) ribosomal protein synthesis is involved in cell growth activation. These results together with a consideration of the pertinent literature allow us to formulate a hypothesis on the control of cell division in mammalian cells. DNA synthesis might be the terminal event in a chain of metabolic processes whereby a cell adjusts itself to increased functional demands (Increased Functional Demand Hypothesis). The main points of this model are the following: the interaction of the extracellular effector on the target cells first activates the pre-existent protein-synthesizing apparatus of the cell, which in turn brings about the activation of the "translation-transcription connecting mechanism" whereby the cells adjusts itself to an increased need for protein synthesis. Such a mechanism is characterized by cytoplasmic signals arising from the protein-synthesizing apparatus of the cell which reach the nucleus and call forth a messenger RNA for ribosomal proteins. The latter, once synthesized, protect the nascent ribosomal RNA from nuclease attack, resulting in an accumulation of ribosomes in the cytoplasm. Once the ribosomes have reached a "critical amount", the cell is triggered to enter DNA synthesis. As a link between the enhanced ribosomal RNA synthesis and DNA synthesis a reduction in the capacity of the ribonucleotide pool as source of DNA precursors has been suggested.