Role of cyclic nucleotides in cell growth and differentiation.

A simple model is depicted below that suggests some unifying principals in the action of cyclic nucleotides in the GO-to-G+ interconversion, differentiation, and transformation (see article). The letters with G+ subscripts (AG+ through EG+) represent cell states at different increasing levels of "determination" (see sect. vE). Cells in each of these states are continuously reproducing themselves through cell division (i.e., they are in G+). As an alternative to cell reporduction, cells at each level may move toward or enter GO, which is conceived of not only as a quiescent state but also as a state in which differentiated properties are more fully expressed. This state is designated by letters with GO subscripts (AGO through EGO). Entrance into this more expressed state will usually be reversible (nerve cells and red blood cells are two exceptions). Sometimes movement toward GO and full expression may require a number of cell divisions. Ultimately, however, there usually will be a slowing or cessation of cell division. The transformed state, according to this model, is one in which cells have lost the ability to enter the "expressed" CO state. However, they do remain differentiated in the sense that they have maintained their level of determination and can be induced to enter into the expressed state, as for example in the case of DBcAMP treatment of transformed fibroblasts. In most cases, cAMP appears to stimulate cells to proceed toward XGO (where X = A,B,C,D, or E) and toward fuller expression of their differentiated functions. It is not the sole mediator of this transition. In cell types where cAMP plays this role, transformation may arise through a defect in the ability to raise cAMP levels in response to growth-regulatory signals or in a defect in the cell's ability to respond to cAMP. In other cell types, cAMP may not be involved in the CO-to-C+ transition or may act in the opposite direction (see sect. II). It remains to be seen whether these situations are ture exceptions or whether different loci of regulation are involved. For example it is possible that in certain cases where cAMP has been shown to stimulate growth that it is stimulating growth toward a more expressed state. Other actions of cAMP relating to cell-cycle traverse have been discussed (sect. III). Investigations of the action of cGMP are still at a preliminary stage of development. There is evidence consistent with the idea that cGMP mediates conversion toward the G+ state in some cell types (see sect. II) under certain conditions. However, further studies are required to establish this as a fact. There has been little or no reported evidence relating to a role for cGMP in expression of differentiated properties, nor has there been any significant evidence as yet for other cell-cycle roles of cGMP. It should be apparent that the areas of biology covered in this review are only beginning to evolve biochemically...