Molecules involved in proliferation of normal and cancer cells: presidential address. (1987)

All definitions of cancer stress the defective regulation of cell growth and differentiation because such physiological aberra tions underlie the gross derangements of the disease. An im portant goal of basic cancer biology is to provide molecular explanations for these defective cellular processes. With recent developments in molecular and cellular biology, investigators have obtained penetrating insights into cell processes and their respective derangements. These are being investigated at four experimental levels: genes and their mRNAs; growth factors and their receptors; biochemical regulation; and cell biology in culture. The results are interrelated and integrated within the framework of the classical cell proliferation cycle. Cell proliferation, the creation of two cells from one, is the culmination of a vast number of biochemical events which are needed to duplicate all of a cell's components. Among these processes in the cell only a few are regulating pacemakers; the rest are controlled although they may be essential for growth. It is extremely important to our further understanding of growth control to discover the regulating events and the mole cules involved in them. Current studies demonstrate that there are a limited number of such events, located at definite points in the cell cycle. These regulatory processes are deranged in cancer cells; they are the ones on which our research focuses. Within the context of these general thoughts, research from our laboratory and others has led to several conclusions. A major regulatory control occurs prior to the entry of cells into S phase. This event appears to regulate not only the onset of DNA synthesis but other events which take place simultane ously, such as syntheses of histones and specific enzymes in volved in DNA synthesis (e.g., thymidine kinase). Cells are committed to complete their DNA duplication about 2 h before the onset of S phase. At this point (the restriction point) they can go on to make DNA in the absence of external growth factors. Proliferation is thus controlled by events during d rather than by processes occurring during the S, G2, or M portions of the cell cycle. These latter cycle stages are terminal and necessary for production of a new cell but they appear much less dependent upon regulatory molecular processes than are G0 and GA¬ events. Some regulation-related events occurring prior to the restric tion point have been identified. IGF-12 is the only growth factor required by BALB/c 3T3 fibroblasts in the interval from 2 to 6 h prior to S phase. During this same time the ras oncogene is activated to produce its message. Studies with inhibitors show that cells cannot initiate S phase without rapid protein synthesis during this prerestriction point interval. The data strongly suggest that normal cells need to make a critical amount of a particular protein that is quite unstable, having a half-life of about 2.5 h, in order to pass the restriction point. Various tumorigenic cells behave as if this protein is stabilized or made in excess, suggesting that greater availability of this protein