Differences in growth regulation of normal and tumor cells.

Normal cells cannot initiate DNA synthesis under inadequate external conditions, yet after growth has started they complete their division cycle under these conditions. The sensitive biochemical event for a growing cell is proposed to be accumulation of a labile protein which in adequate amounts permits entry into S phase, after about 2 hr, and completion of the cycle. Instability of this protein (half-life about 2.5 hr) creates a dynamic state so that its accumulation depends on rates of both synthesis and degradation. Neoplastic cells may show poorly regulated growth either by synthesizing this protein more rapidly or degrading it less rapidly, under conditions that limit normal cells' growth. Known mechanisms of overproduction include: more copies of the protein's structural gene per cell, an adjacent high-activity promoter, or autoproduction of growth factors. Less rapid degradation could result from less protease activity or from stabilizing modifications of the protein. Thus, derangement in the control of a labile growth-regulatory protein acting by any one of these diverse mechanisms could lead to neoplasia.