Control of cell proliferation by progress in differentiation: clues to mechanisms of aging, cancer causation and therapy.

In multicellular organisms, the control of cell proliferation occurs, in part, by modulating the progress in differentiation. In normal and neoplastic cells, for example, progress towards terminal differentiation concludes cell proliferation, whereas arrest of progress in differentiation causes uncontrolled cell proliferation. Evidence is presented according to which the progress in differentiation depends on an increase in the ratio between mitochondrial differentiation promoting activity and nuclear differentiation preventing activity. This ratio is low in embryonic cells and in stem cells, due to low mitochondrial content, but increases by a rate of mitochondrial multiplication that is larger than a doubling of mitochondrial content per cell cycle. The rate of mitochondrial multiplication, thus, decides on the progress in differentiation and controls the number of amplification divisions between cell determination and terminal differentiation. This rate is modifiable by extracellular signals and cellular defects. Mutations, for example in nuclear genes coding for mitochondrial proteins, are likely to decrease the rate so much that differentiation is arrested with ensuing neoplastic growth. Agents used in differentiation therapy and ionizing radiation overcome this arrest: the cell cycle is sensitive to these agents, but not the mitochondria which multiply during the transitory cell cycle inhibition, thus increasing the differentiation promoting activity. Differentiation arrest can be circumvented also by direct inhibition of nuclear differentiation preventing activity at the level of transcription or translation, whereas corresponding inhibition of mitochondrial differentiation promoting activity prevents differentiation. Accumulation of non-specific genetic damage causes persisting cell cycle prolongation and enhancement of differentiation which, apparently, are involved in senescence. The recent finding of increase in mitochondrial mass prior to release of cytochrome c, induction of differentiation, and apoptosis points to similarities in the initial molecular pathways of differentiation and apoptosis.